6-amino-1, 2-dihydro-1-hydroxy-2-imino-4-phenoxypyrimidines



United States Patent Ofifice 3,382,2476-AMINO-1,2-DlI-IYDRO-1-HYDROXY-2-IMINO- 4-PHENOXYPYRIMIDINES William C.Anthony, Kalamazoo, and Joseph J. Ursprung, Portage, Mich., assignors toThe Upjohn Company,

Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Nov. 1,1965, Ser. No. 505,989 5 Claims. (Cl. 260256.4)

ABSTRACT OF THE DISCLOSURE 6amino-1,Z-dihydro-l-hydroxy-2-imino-4-phenoxypyrimidines and thecorresponding acid addition salts are disclosed. These compounds areuseful as antihypertensive agents, blood pressure lowering agents, andas agents for the treatment of shock.

This invention relates to novel compositions of matter and to methodsfor producing them. In particular, this invention relates to novel1,Z-dihydro-1=hydroxypyrimidines of the formula:

on N HZN I :NH

wherein R is a moiety selected from the group consisting of moieties ofthe formula wherein R and R are selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower aralkyl, and lowercycloalkyl, with the proviso that both R and R are not hydrogen, and theheterocyclic moieties, aziridinyl, azetidinyl, pyrrolidinyl, piperidino,hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino,and 4-lower-alkylpiperazinyl, each of said heterocyclic moieties havingattached as substituents on carbon atoms, thereof zero to 3 loweralkyls, inclusive, a nitrogen atom of each of said heterocyclic moietiesbeing the point of attachment of R to the ring in said formula. When R1IS R and R, can be alike or different. When R is a heterocyclic moiety,the alkyls which can be attached thereto can all be diiferent or any twoor all of them can be alike.

3,382,247 Patented May 7, 1968 R in Formula I is a imonovalent moietywhich can be the same as or different than R Although R can be any of alarge variety of atoms or groups of atoms, this invention relatesespecially to compounds of the formulas:

on on N /N H2N T=NH HzN) W=NH R2- N Br t/ on N mN W=NH in IV wherein, ineach instance, R is as defined above.

.In Formula II, R is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower alkoxyalkyl, lower cycloalkyl, loweraryl, lower aralkyl, lower alkaryl, lower alkaralkyl, loweral-koxyaralkyl, and lower haloaralkyl. In Formula III, R is selectedfrom the group consisting of chlorine, bromine, iodine, nitroso, nitro,amino, phenylt'hio, lower alkylphenylthio, and halophenylthio. InFormula IV, R,- is assigned the same definition as R above. R can be thesame as or different than R within the scope of that definition.

The novel 1,Z-dihydro-l-hydroxypyrimidines of this invention can berepresented by formulas other than Formulas I, II, III, and IV. Forexample, with regard to Formula I, among such other formulas are:

Compounds of Formulas IA and IB are tautomeric with compounds of FormulaI. For convenience, reference will be made hereinafter only to FonmulasI, II, III, and IV. It is to be understood, however, that the novelcompounds of this invention are likely to be mixtures of tautomericforms, the compositions of which are dependent on such factors as thenature of R R R and R and the environment. In some instances, one formor another may predominate.

Examples of lower alkyl are methyl, p y ethyl, 516x34, p py p y butyl,octyl,

and isomeric forms thereof.

3,3-diethylheptamethylenimino, 2,5,8-trimethylheptamethylenimino,S-methyloctamethylenimino, 2,9-diethyloctamethylenimino,4-isooctyloctamethylenimino, 2-ethylmorpho1ino,2-methyl-5-ethyhnorpholino, 3,3-dimethylmorpholino,2,6-di-tert-butylmorpholino, 4-methylpiperazinyl,4-isopropylpiperazinyl,

and the like. In each of the above examples of heterocyclic moieties,the free valence, and hence the point of attachment to a carbon atom ofthe pyrimidine ring, is at the heterocyclic nitrogen atom.

The novel 1,2-dihydro-l-hydroxypyrimidines of Formulas I, II, III, andIV are amines, and exist in the nonprotonated or free base form, or inthe protonated or acid addition salt form, depending on the pH of theenvironment. They form stable protonates, i.e., monoor diacid additionsalts, on neutralization with suitable acids, for example, hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, acetic, benzoic, salicylic,glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic,methanesulfonic, cyclohexanesulfamic, picric, and lactic acids, and thelike. These acid addition salts are useful for upgrading or purifyingthe free bases. The free bases are useful as acid acceptors inneutralizing undesirable acidity or in absorbing an acid as it is formedin a chemical reaction, for example, a dehydrohalogenation reaction inwhich hydrogen and chlorine, bromine, or iodine are removed from vicinalcarbon atoms.

The novel Formulas I, II, III, and IV compounds form salts withfiuosilicic acid which are useful as mothproofing agents according toUS. Patents 1,915,334 and 2,075,359. They also form salts withthiocyanic acid which condense with formaldehyde to form resinousmaterials useful as pickling inhibitors according to US. Patents2,425,320 and 2,606,155.

The Formulas I, II, III, and IV 1,2-dihydro-l-hydroxypyrimidines of thisinvention also form salts with penicillins. These salts have solubilitycharacteristics which cause them to be useful in the isolation andpurification f penicillins, particularly benzyl penicillin. Said saltscan be formed either by neutralization of the free base form of acompound of Formula I, II, III, or IV with the free acid form of apenicillin, or by a metathetical exchange of the anion of an acidaddition salt of a Formula I, II, III, or IV compound, for example, thechloride ion of a hydrochloride, with the anionic form of a penicillin.

The novel Formulas I, II, III, and 1V 1,2-dihydro-1- hydroxypyrimidinesalso form carboxyacylates on treatment with carboxyacrylating agents,for example, carboxylic acid anhydrides and carboxylic acid chlorides.These carboxyacylates can be single compounds or mixtures of compoundsdepending on such factors as the nature of the1,Z-dihydro-l-hydroxypyrimidine reactant, the carboxylacylating agent,and the reaction conditions.

carboxyacylates obtained from Formula I 1,2-dihydrol-hydroxypyrimidinescan be represented by the formula:

wherein R and R are as defined above. It is especially preferred that Rinclude R R and R as those are defined above. A A and A are eachselected from the group consisting of hydrogen and carboxyacyl, with theproviso that at least one of A and A is carboxyacyl.

The carboxyacylates of Formula V can be used for upgrading a Formula I,II, III, or IV 1,2-dihydro-1-hydroxypyrimidine free base. The latter canbe transformed to a carboxyacylate, the carboxyacylate purified byconventional techniques, e.g., recrystallization or chromatography, andthe purified carb'oxyacylate deacylated, advantageously by alcoholysis.

The dihydropyrimidine carboxyacylates of Formula V can be represented byother formulas. As for Formula I compounds, these Formula Vcarboxyacylates are likely to be mixtures of tautomeric forms, thecompositions of which are dependent on such factors as the nature of thesubstituents and the carboxyacyl moieties, and the environment. In someinstances, one form or another may predominate. Formula V is used forconvenience, and the other tautomeric forms are not excluded.

Carboxyacylates of Formula V are amines and exist in either thenonprotonated (free base) form or the protonated (acid addition salt)form depending upon the pH of the environment. They form stableprotonates on neutralization with suitable strong acids, for example,hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, andthe like. These acid addition salts are useful for upgrading orpurifying the carboxyacylate free bases.

The novel compounds of this invention, including the free bases ofFormulas I, II, III, and IV, the acid addition salts thereof, thecarboxyacylates of Formula V, and the acid addition salts thereofpossess pharmacological activity. For example, they are orally andparenterally active in birds and mammals, including man, asantihypertensive agents having vasodilatory activity, and are useful forlowering blood pressure and for the treatment of shock. They are alsouseful as antifertility agents, as antiviral agents, asanti-inflammatory agents, and as central nervous system stimulants.These compounds also cause electrolyte and water retention in laboratoryanimals such as rats and dogs, and hence are useful to producelaboratory animals with larger than normal amounts of sodium ions,potassium ions, chloride ions, and water. Such animals are useful inpharmacological research, for example, in screening compounds forpossible diuretic activity and in studying the action of knowndiuretics.

The compounds of Formula II, for example, wherein R is hydrogen or loweralkyl and R is dimethylamino, pyrrolidinyl, or piperidino are especiallypotent as antihypertensive agents in mammals, including man.

The novel 1,2-dihydro-1-hydroxypyrimidines of Formula II are produced bymixing a compound of the formula:

wherein X is selected from the group consisting of fluorine, chlorine,and bromine, and n is zero to 3, inclusive, and wherein R is as definedabove, with an amine of the formula R I-I, wherein R is as definedabove. The phenoxy moiety of the Formula VI reactant is displaced by theR moiety of the amine.

The 1,2 dihydro 1-hydroxy-4-phenoxypyrimidines of Formula VI are novelcompounds. In addition to being useful as reactants for the productionof Formula II 1,2-

V II

wherein X, n, and R are as defined above, with a percarboxylic acid.Particularly preferred for this purpose are perbenzoic acids of theformula:

V III wherein Z is selected from the group consisting of halogen, loweralkyl, lower alkoxy, and nitro, and n is zero to 5, inclusive. However,other percarboxylic acids can be used for this oxidation, examples beingperformic acid, peracetic acid, perpropionic acid, perbutyric acid,perphthalic acid, percamphoric acid, and the like.

Pyrimidines of Formula VII are prepared by mixing a pyrimidine of theformula:

N H N- wherein R is as defined above, with a phenoxide salt of a phenolof the formula:

wherein X and n are as defined above.

2,4-diamino-6-chloropyrimidines of Formula 1X are known in the art orcan be prepared by methods known in the art. For example, they can beprepared by the following reaction sequence, wherein R is as definedabove and R is hydrogen or alkyl:

See, for example, I. Am. Chem. Soc. 72, 1914 (1950); Chem. Ber. 94, 12(1961); Organic Syntheses, Coll. vol. 4, 245 (1963); and US. Patent2,673,204. Illustratively, guanidine and ethyl cyanoacetate are reactedin the presence of sodium ethoxide to give2,4-diamino-6-hydroxypyrimidine. That product is then reacted withphosphorus oxychloride to give 2,4-diamino-6-chloropyrimidine.Similarly, guanidine is reacted with ethyl ot-cyanopropionate, ethyla-cyanophenylacetate, and ethyl Ot-CYfiHO-fi-PhEIIYlpropionate to give2,4-diamino-5-methyl-G-hydroxypyrimidine,2,4-diarnino-5-phenyl-G-hydroxypyrimidine, and 2,4-diamino-5-benzyl-G-hydroxypyrimidine, respectively. Each of those 2,4diamino S-substituted-fi-hydroxypyrimidines is then transformed to thecorresponding 2,4-di amino-5- substituted-fi-chloropyrimidine byreaction with phosphorus oxychloride.

Formula IX 2,4-diamino-6-chloropyrimidines can also be prepared by thefollowing reaction sequence, wherein R is as defined above:

N zN Ely-NH:

See, for example, Ber. Deut. Chem. Ges. 34, 3362 (1901); ibid., 38, 3394(1905); ibid., 45, 3124 (1912); ibid., 52, 869 (1919); J. Chem. Soc.(London), 3439 (1951); and British specification 710,070.Illustratively, barbituric acid is reacted with phosphorus oxychlorideto give 2,4,6-trichloropyrimidine which is then reacted with ammonia togive 2,4-diamino-6-chloropyrimidine. Similarly, S-methylbarbituric acid,S- henylbarbituric acid, and S-benzylbarbituric acid are reacted withphosphorus oxychloride to give 2,4,6 trichloro-5-methylpyrimidine,2,4,6-trichloro- 5 phenylpyrimidine, and2,4,6-trichloro-5-benzylpyrimidine, respectively. Each of those2,4,6-trichl0r0-5-substituted pyrimidines is then reacted with ammoniato give the corresponding 2,4-diamino-5-substituted-6-chloropyrimidine.

The barbituric acid reactants in the above reaction sequence are knownor can be prepared by known methods.

The novel 1,2-dihydro-l-hydroxypyrimidines of Formula III wherein R isnitroso or nitro can be produced by either of two different reactionsequences. A Formula II 1,Z-dihydro-l-hydroxypyrimidine wherein R ishydrogen is nitrosated or nitrated. Alternatively, a Formula VI 1,2dihydro 1-hydroxy-4-phenoxypyrimidine wherein R is hydrogen isnitrosated 0r nitratetl, the phenoxy moiety of product thus obtainedthen being displaced with an amine of the formula R H, wherein (IJH HaNN NH HONUz HONO' (RH DH H N NYNH HgN I N XII 2M 0N 1 R1 T R1H (13H OH HN N NH HzN i i 1 N xv N 02M X 0N During nitration of Formula XIV1,2-dihydro-1-hydroxy-4-phenoxypyrimidines, there is a tendency for thephenoxy moiety to be nitrated. A nitro substituent in the phenoxy moietysometimes interferes with a subsequent displacement of the entirephenoxy moiety with a monoor disubstituted amino moiety as in theproduction of Formula XII pyrimidines. For that reason, it is usuallypreferred to produce Formula XII compounds by nitration of Formula XIcompounds rather than by the alternative route.

The novel 1,2-dihydro-1-hydroxypyrimidines of Formula III wherein R isamino can be produced by any of several different reaction sequences. AFormula XII 1,2-dihydro-1-hydroxy-S-nitropyrimidine or a Formula XIII1,2-dihydro-1-hydroxy-5-nitrosopyrimidine is mixed with hydrogen in thepresence of a hydrogenation catalyst. Alternatively, a Formula XV1,2-dihydro-1-hydroxy-5-nitro-4-phenoxypyrimidine or a Formula XVI 1,2dihydro 1-hydroxy-5-nitroso-4-phenoxypyrimidine is mixed with hydrogenin the presence of a hydrogenation catalyst, the phenoxy moiety of theproduct thus obtained then being displaced with an amine of the formulaR H, wherein R is as reaction sequences are as follows:

defined above. These 2, catalyst catalyst the Formula XVI5-nitroso-4-phenoxypyrimidine followed by displacement of the phenoxymoiety with an OH H HzN i i NH i XII U X l I I HzN I i NH H2" NH I :L xvI T XVI 02M n ON n Quite unexpectedly, the carbon-carbon andcarbonnitrogen unsaturation in the 1,2-dihydropyrimidine ring is nothydrogenated with the same ease as the nitroso or nitro moiety.Therefore, the hydrogenation conditions can easily be selected tohydrogenate only the nitroso or nitro moiety. It should be noted,however, that 5- aminopyrimidines of Formula XVII wherein R contains analkenyl moiety cannot be prepared by catalytic hydrogenation of FormulaXII S-nitropyrimidines or Formula XIII S-nitrosopyrimidines because analkenyl moieties will be transformed by hydrogenation to alkyl moieties.Formula XVII S-aminopyrimidines with carbon-carbon unsaturation in the Rmoiety can, however, be prepared by the alternative route, i.e.,reduction of the Formula XV 5-nitro-4-phenoxypyrimidine or amine, R H,which can contain carbon-carbon unsaturation. Alternatively, the nitrosomoiety in the Formula XVI or XIII compounds or the nitro moiety in theFormula XV or XII compounds can be reduced by a chemical reducing agentwhich does not alter carboncarbon unsaturation, for example, sodiumdithionite or sodium hydrosulfite. See, for example, J. Chem. Soc.(London) 985 (1956); I. Am. Chem. SOC. 79, 1518 (1957); Ber. Deut. Chem.88, 1306 (1955); ibid. 89, 2799 (1956); ibid. 90, 2272 (1957).

The novel l,2-dihydro-l-hydroxypyrimidines of Formula III wherein R ischlorine, bromine, or iodine are produced by the following reactionsequence, wherein R X, and n are as defined above, and Y is chlorine,bromine, or iodine:

13 14 HEN Ha halogenation HEN I agent I u Y n o 0 XIX XX percarboxyl icacid Y Y n XXll Suitable percarboxylic acids for the transformation ofFormula XX pyrimidines to Formula XXI 1,2-di1hydro-1- hydnoxypyrimidinesare those listed above as suitable for the transformation of Formula VIIpyrimidines to Formula VI 1,2-dihydro-l-hydroxypyrimidines. Especiallypreferred for this purpose are the above-mentioned perbenz-oic acids ofFormula V III. Suitable halogenation agents are the halogens themselves,i.e., chlorine, bromine, and iodine, and the so-called positive halogencompounds.

The term, positive halogen compound, as used herein, refers to organicor inorganic compounds which contain chlorine, bromine, or iodine with avalence number +l1. Such compounds usually contain a chlorine, bromine,or iodine atom bonded to some other atom, usually oxygen or nitrogen, inan inorganic or organic compound by a polar covalent bond wherein thehalogen atom is the positive end of the dipole. Examples of inorganicpositive halogen compounds are the hypoh'alous acids, e.g., hypochlorousacid and hypobromous acids, and the hypohalites, e.g., lithium, sodium,potassium, and calcium hypochlorites, hypobromites, and hypoiodi-tes.Examples of organic positive halogen compounds are hypohalite esters,e.g., t-butyl hypochlorite; 'N-haloamides, e.g., 'N-chloroacetamide,N-bromoacetamide, N- bromobenzamide, N,p dichloroacetanilide, Nchlorop-nitroacetanilide, and N-chlorobenzenesulfonamide;

Z ESQ wherein Z is hydrogen, lower alkyl, or halogen, i.e., fluorine,chlorine, bromine, or iodine.

The novel 1,2dihydro-l-hydroxypyrimidines of Formula IV are produced bymixing a 1,2-dihy-droa1-hydroxy-5-halopyrimidine of Formula XXII with anamine of the Formula R H, wherein R is as defined above.

These last two reactions can be formulated as follows:

XXIII iJH HaN N NH l XXH 1H ii NH Hall Y T xxlv i /N Ra 15 wherein R Rand Y are as defined above, and R is selected from the group consistingof phenylthio, loweralkylphenytlhio, and halophenylthio. R 'H representsthe same compounds as Formula XXIII. R in the amine R I-I can be thesame as or different than R The reaction between a Formula IX2,4-diamino-6- chloropyrimidine and a phenoxide salt of the Formula Xphenol is carried out by heating a mixture of the pyrimidine and thesalt in the range about 100 to about 200 0, preferably in the rangeabout 140 to about 180 C., until the desired displacement reaction takesplace. Usually about one to about 10 hours of heating is sufficient,less time usually being required at 180 C. than at 140" C.

*Alkali metal phenoxides, especially sodium or potassium phenoxides, are.preferred although phenoxides of other metals, e.g., magnesium,calcium, and aluminum, can be used. One molecular equivalent of thephenoxide salt is required to react with each molecular equivalent of2,4-diamino-6-chloropyrimidine, and there is usually no reason to useother than those molecular proportions. It is advantageous, however, toheat the phenoxide salt and the 6-chloropyrimidine in the presence ofabout one to about 10 or even more molecular equivalents of the phenolcorresponding to the phenoxide salt. The phenol then serves as adiluent, and can also serve as a source of the phenoxide salt. In thelatter case, one molecular equivalent of a metal hydroxide correspondingto the desired metal phenoxide salt, e.g., sodium hydroxide or potassiumhydroxide, is added to sufficient Formula X phenol to produce thedesired amount of phenoxide salt and leave enough to serve as thediluent.

In preparing the mixture of phenoxide salt and phenol diluent, it isoften advantageous to add the metal hydroxide in solid form, and thenremove water by a preliminary heating at about 100 C. Thechloropyrimidine is then added to the phenoxide-phenol mixture.

Alternatively, chloropyrimicline, metal hydroxide, and sufficient phenolto form .phenoxide and to serve as a diluent are mixed together andheated.

In place of or in addition to a phenol diluent, another inert liquiddiluent, for example, dimethylformamide, can be used to aid in forming asuitably mobile reaction mixture.

The desired Formula VII 2,4-diamino-6-phenoxypyrimidine can be isolatedfrom the reaction mixture by conventional methods, for example, baddition of sufiicient aqueous alkali metal hydroxide solution todissolve the phenol diluent, if one is used, followed by separation ofthe desired product by filtration or centrifugation. Thephenoxypyrimidine can then be purified, if desired, by conventionalmethods, for example, by recrystallization from a suitable solvent ormixture of solvents.

The reaction between a Formula VII 2,4-diamino-6- phenoxypyrimidine anda percarboxylic acid to produce a Formula VI1,2-dihydro-1-hydroxy-4-phenoxypyrimidine is carried out by mixing thosetwo reactants, preferably in the presence of an inert liquid diluent.Although, as mentioned above, percarboxylic acids generally are usefulfor this oxidation, it is preferred to use perbenzoic acids of FormulaVIII. Acids of Formula VIII are known in the art or can be prepared bymethods known in the art. See, for example, Braun, Organic Syntheses,Coll. vol. 1, 2d ed., 431 (1941) and Silbert et al., J. Org. Chem. 27,1336 (1962). In Formula VIII, when n is 2 or more, the Zs can be thesame or different. Examples of halogen are fluorine, chlorine, bromine,and iodine. Examples of lower alkyl are methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. Examples oflower alkoxy are methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,heptyloxy, octyloxy, and isomeric forms thereof. Illustrative oxidizingacids of Formula VIII include perbenzoic acid, m-, and p-chloroandbromoperbenzoic acids, 3,5 dichloroperbenzoic acid,2,3,5,6-tetrachloroperbenzoic acid, 4-methylperbenzoic acid,3,4-dimethylperbenzoic acid, pentamethylperbenzoic acid, o-, m-, andp-methoxyperbenzoic acids, 3-nitroperbenzoic acid, 2,4-dinitroperbenzoicacid, 3-chloro-4- methoxyperbenzoic acid, 3-chloro-4-nitroperbenzoicacid, and the like.

In carrying out the reaction between the Formula VII pyrimidine and theFormula VIII perbenzoic acid, the two reactants are mixed advantageouslybelow about C., preferably between about 10 and +10 0, although higheror lower temperatures can be used. It is preferred to mix the reactantsin the presence of an inert liquid diluent and to stir the mixture untilthe reaction is substantially complete. The reaction usually requiresabout one to about 8 hours. Suitable diluents includeN-loweralkylpyrrolidones, e.g., N-methylpyrrolidone; lower alkanols,e.g., methanol, ethanol, propanol, isopropyl alcohol, the butanols andthe pentanols; lower alkanol and glycols esters of lower alkanoic acids,e.g., ethyl acetate, butyl acetate, pentyl acetate, ethylene glycolmonoacetate, diethylene glycol monoacetate; ethers, e.g., diethyl ether,diisopropyl ether, ethylene glycol monoethyl ether, diethylene glycolmonobutyl ether; and the like. The molecular ratio of Formula VIIpyrimidine and Formula VIII perbenzoic acid can be varied widely. Ratiosfrom about 1:1 to 1:5, preferably from about 1:1.5 to 1:25, aresuitable.

In many cases, Formula VII pyrimidines wherein R is lower alkenyl can beoxidized to the corresponding Formula VI1,2-dihydro-l-hydroxypyrimidines without double bond epoxidation,particularly when the double bonds are part of lower Z-alkenylgroupings. If the double bonds are not resistant to epoxidation, theycan be protected before and regenerated after the oxidation. Forexample, a double bond can be brominated, the compound oxidized, and thedouble bond regenerated by treatment with zinc metal in a solvent suchas ethanol. Alternatively, epoxidation can be allowed to occur and theepoxy group transformed back to a double bond. An example is theprocedure of Cornforth et al., J. Chem. Soc. 112 (1959), involvingtreatment of an epoxide with a mixture of sodium iodide, sodium acetate,zinc, and acetic acid. Other methods of producing Formula VI compoundswherein R is lower alkenyl involve starting with Formula VII pyrimidineswherein an R carbon atom is attached to a halogen, e.g., bromine oriodine, another carbon atom vicinal to that carbon atom being attachedto a lower alkoxy, e.g., methoxy, or to a carboxyl. After the oxidation,the halogen plus lower alkoxy are removed by zinc treatment [Dykstra etal., J. Am. Chem. Soc. 52, 3396 (1930)], or the halogen plus carboxylare removed by sodium carbonate treatment [Young et al., J. Am. Chem.Soc. 51, 2528 (1929)]. Other methods of protecting, regenerating, orintroducing carbon-carbon double bonds to produce desired Formula VI1,2-dihydro- 1-hydroxy-4-phenoxypyrimidines wherein R is lower alkenylwill be apparent to those skilled in the art.

The 1,2 dihydro 1-hydroxy-4-phenoxypyrimidine of Formula VI can beisolated from the oxidation reaction mixture by conventional techniques,for example, by successive evaporation of the reaction solvent atreduced pressure, solution of the basic Formula VI product in aqueousacid, e.g., hydrochloric acid, removal of undesired water-insolublereaction products by filtration, neutralization of the acidic filtrate,and isolation of the Formula VI product by filtration, extraction, orchromatography. The isolated material can be purified by conventionaltechniques, for example, by recrystallization from a suitable solvent orpair of solvents, or by preparation of an acid addition salt, e.g., thehydrochloride or acid phosphate, and recrystallization of the salt,followed, if desired, by reconversion of the salt to the free base inthe usual manner.

The reaction between a Formula VI 1,2-dihydro-1-hydroxy-4-phenoxypyrimidine and an amine of Formula R H, wherein R is asdefined above, to produce a Formula II, 1,2-dihydro-l-hydroxypyrimidineis carried out by mixing those two reactants and heating the mixture inthe range about 100 to about 200 0., preferably in the range about 125to about 175 C. at least one molecular equivalent of the amine should bemixed with each molecular equivalent of the pyrimidine reactant. It isusually advantageous to use an excess of the amine, for example, about 2to about 20 molecular equivalents or even more of amine per molecularequivalent of'the pyrimidine, the excess amine then acting as a diluent.An inert organic diluent can also be present in the reaction mixture.Especially suitable for that purpose are dialkylformamides, particularlythose where the dialkyl substituents are the same as those on thedisplacing amine, and alkanols.

When the reactant amine has a relatively low boiling point and is likelyto escape from the reaction vessel during heating, it is advantageous touse a closed reaction vessel, for example, a heavy-wall, sealed, glasstube or a closed metal autoclave for the heating step.

A reaction time of about one to about 20 hours is usually required. Thedesired displacement reaction usually takes place more rapidly at highertemperatures than at lower. Moreover, when the phenoxy moiety has 2 or 3halogen substituents, i.e., when n in Formula VI is 2 or 3, thedisplacement usually takes place more rapidly and at a lower temperaturethan when fewer or no halogen is present. In the latter instances,especially when no halogen is present in the phenoxy moiety, thedisplacement reaction is often accelerated by adding sodium or potassiummetal to the reaction mixture. Preferably, about one atomic equivalentof the alkali metal is added per molecular equivalent of the pyrimidinereactant. Addition of a catalytic amount of a Lewis acid such as ferricchloride with the alkali metal will also often accelerate thedisplacement reaction or make feasible a lower reaction temperature.About 0.01 to 0.001 molecular equivalents of ferric chloride per atomicequivalent of alkali metalis usually a suitable catalytic amount.Examples of suitable primary amine reactants for this displacementreaction are methylamine, ethylamine, propylarnine, isopropylamine,butylamine, sec-butylamine, pentylamine, isopentylamine, hexylamine,heptylamine, octylamine, allylamine, 2-methylallylamine, 2-butenylamine,Bbutenylamine, 3-pentenylamine, 4-hexenylamine,4,4-dimethyl-Z-pentenylamine, cyclo'butylamine, cyclohexylamine,4-tert-butylcyclohexylamine, benzylamine, phenethylamine, and the like.Examples of suitable secondary amines for this purpose aredimethylamine, diethylamine, N-rnethylethylamine, dipropylamine,N-ethylisopropylamine, di-sec-butylamine, N-methylbutylamine,dipentylamine, N-et-hyl-Z,4-dimethylpentylamine, N-methyloctylamine,diheptylamine, diallylamine, N-methylallylamine, di-( l-methylallyl)amine, di-(Z-methylallyl) amine, N-ethyl-l-methylallylamine,N-propyl-2-ethylallylamine, di-(2-pentenyl)amine, di-(3-butenyl)amine,di-(4-hexenyl)amine, N-butyl-Z-butenylamine, N-methylcyclohexylamine,dicyclohexylamine, N-ethyl-benzylamine, dibenzyla-mine,di(4-methyl-3-hexenyl)amine, aziridine, 2- methylaziridine,2,2-dimethylaziridine, azetidine, 2-ethylazetidine, 3-octylazetidine,3,3-dimet-hylazetidine, 2,2,4- trimethylazetidine, pyrrolidine,2-propylpyrrolidine, 3- butylpyrrolidine, 2-isohexylpyrrolidine,2,3-dimethylpyrrolidine, 2,2,4-trimethylpyrrolidine,2,5-diethylpyrrlidine, 3,4-dioctylpyrrolidine, piperidine,Z-methylpiperidine', 3- ethylpiperidine, 4-butylpiperidine,2,4,6-trimethylpiperidine, Z-methyl-S-ethylpiperidine,3,5-dipentylpiperidine, hexahydroazepine, Z-ethylhexahydroazepine,4-tert-butylhexahydroazepine, 3,3-dimethylhexahydroazepine, 2,4,6-tripropylhexahydroazepine, heptamethylenimine,2-methylheptamethylenimine, 2,4 diisopropylheptamethylenimine,octamethylenimine, 4-isooctyloctamethylenimine, morpholine,2-ethylmorpholine, 2-methyl-S-ethylmorpho- 18 line,2,6-dimethylmorpholine, N-methylpiperazine, and the like.

The desired Formula II 1,2-dihydro-l-hydroxypyrimidine can usually beisolated from the reaction mixture in free base form by cooling thereaction mixture to about 0 to about 25 C. The free base form usuallyprecipitates and can be isolated by conventional techniques, forexample, by filtration or centrifugation. Alternatively, excess amineand other diluent, if one is used, can be removed by distillation orevaporation, and the desired 1,2-dihydro-l-hydroxyprimidine isolated byconventional techniques, for example, fractional recrystallization orextraction. The isolated pyrimidine can then be purified, if desired, byconventional techniques, for example, recrystallization from a suitablesolvent or mixture of solvents, or by chromatography. Alternatively, anacid addition salt, e.g., the hydrochloride or acid phosphate of thepyrimidine product can be prepared, purified by recrystallization, andthen, if desired, reconverted to the free base in the usual manner.

Nitrosation of the Formula XI 1,2-dihydro-1-hydroxypyrimidines andFormula XIV 1,2-dihydro-l-hydroxy-4- phenoxypyrimidines isadvantageously carried out by mixing the pyrimidine reactant with astrong acid, and then adding a nitrite salt, preferably sodium nitrite,to the mixture with cooling. Concentrated sulfuric acid is the preferredstrong acid. About one molecular equivalent of the nitrite salt shouldbe used for each molecular equivalent of the pyrimidine reactant. Areaction temperature in the range about 0 to about 25 C. is preferred.It is advantageous to add an aqueous solution of the nitrite salt to theacid solution of the pyrimidine.

The desired nitrosation usually takes place within about 15 minutes toabout 4 hours in the preferred temperature range. After the nitrosationis complete, the desired nitroso compound can be isolated by dilutingthe reaction mixture with water and neutralizing the acid with a base,preferably keeping the mixture below about 25 C. by addition of ice. Anybase can be used but sodium hydroxide, sodium carbonate, or sodiumbicarbonate are preferred. The nitroso product is usually a solid andcan be isolated by conventional methods, for example, by filtration orcentrifugation, and can be purified, if desired, by recrystallizationfrom a suitable solvent or mixture of solvents.

Nitration of the Formula XI 1,2-dihydro-1-hydroxypyrimidines and FormulaXIV 1,2-dihydro-1-hydroxy-4- phenoxypyrimidines is advantageouslycarried out by mixing the pyrimidine reactant with concentrated sulfuricacid cooling the resulting solution, and then slowly adding a mixture ofconcentrated sulfuric acid (95%) and concentrated nitric acid (70%) withcontinued cooling in the range about 0 to about 25 C., preferably about10 to 15 C. A total reaction time of about one to about 5 hours isusually sufiicient. One molecular equivalent of nitric acid is requiredfor each molecular equivalent of pyrimidine reactant unless it isdesired or expected that a phenoxy moiety will be nitrated in a FormulaXIV 1,2-dihydro-l-hydroxy-4-phenoxypyrimidine. In that case twomolecular equivalents of nitric acid should be used. There is usually noreason to use larger amounts of nitric acid.

In some instances, a less concentrated sulfuric acid or lessconcentrated nitric acid can be used if the pyrimidine reactant isespecially easily nitrated. It is also advantageous to do that when itis desired to avoid nitration of the phenoxy moiety of a Formula XIVpyrimidine reactant or an R substituent, for example, an alkenylmoiety.-It will be apparent to those skilled in the art that the optimumnitration conditions for each particular pyrimidine reactant of FormulaXI or Formula XIV, including nitric acid and sulfuric acidconcentrations and amounts, reaction time, and reaction temperature mustbe determined by preliminary small scale experiments.

The nitrated 1,2-dihydro-l-hydroxypyrimidine of Formula XII or XV can beisolated from the reaction mixture by pouring the mixture onto crushedice, making the resulting mixture basic, and then isolating the desirednitration product by conventional methods, for example, filtration,centrifugation, or extraction. The nitration products are usually solidsand can be purified by recrystallization from a suitable solvent ormixture of solvents or by chromatography.

Reduction of the Formula XII or Formula XV 1,2-dihydro-1-hydroxy-5-nitropyrimidines and reduction of the Formula XIIIor Formula XVI 1,2-dihydro-1-hydroxy-5-nitrosopyrimidines isadvantageously carried out by catalytic hydrogenation in the presence ofa hydrogenation catalyst, for example, a noble metal, e.g., platinum,palladium, rhodium, or a base metal, e.g., Raney nickel, Raney cobalt,and in the presence of an inert diluent, for example, methanol, ethanol,dioxane, ethyl acetate, and the like. Palladium catalysts are preferred.

Hydrogenation pressures ranging from about atmospheric to about 100p.s.i., and hydrogenation temperatures ranging from about to about 100C. are preferred.

It is also preferred to add sufficient strong acid, for example, amineral acid such as hydrochloric acid, sulfuric acid, or phosphoricacid, to the pyrimidine reactant before hydrogenation so that theprotonated form of the reactant is hydrogenated and the protonated oracid addition salt form of the S-aminopyrimidine product is produced. Insome instances, the acid addition salt form of the product issubstantially more stable and more easily isolated than the free baseform.

The Formula XVII and Formula XVIII S-aminopyrimidine reduction productsare isolated from the hydrogenation reaction mixtures by conventionaltechniques, for example, by removal of the catalyst by filtration orcentrifugation, and then removal of the diluent by distillation orevaporation. If the S-nitropyrimidine or S-nitrosopyrimidine reactant ispure, it is usually unnecessary to purify the S-aminopyrimidine product.When purification is necessary, however, it is preferred to purify asuitable acid addition salt by recrystallization from a suitable solventor mixture of solvents.

Halogenation of Formula XIX 2,4-diamino-6-phenoxypyrimidines is carriedout by mixing the pyrimidine reactant with the halogenating agent,preferably in the presence of a diluent. For example, in the case ofbromination, the pyrimidine reactant is dissolved in a diluent such asacetic acid, and the resulting solution is gradually mixed in the rangeabout 10 to about 100 C. with one molecular equivalent of bromine, alsodissolved in a diluent such as acetic acid. In some instances, it isadvantageous to carry out the bromination in the presence of Water,although enough organic diluent, e.g., acetic acid, should also bepresent to maintain a homogeneous reaction mixture. The presence of abase such as calcium carbonate, or sodium acetate where the diluent isacetic acid, to neutralize the hydrobromic acid which is formed is alsodesirable. In a similar manner, use of chlorine and iodine yields thecorresponding Formula XX 5-chloropyrimidines and S-iodopyrimidines,respectively. In the case of iodination with iodine, it is advantageousto have present at least one molecular equivalent of a mercuric compoundsuch as mercuric acetate to remove the hydrogen iodide which is formed.

Alternatively, one of the so-called positive halogen compounds, examplesof which have been given above, can be used to halogenate a Formula XIX2,4-diamino-6- phenoxypyrimidine. For example, a mixture of a FormulaXIX pyrimidine reactant, one molecular equivalent of the ositive halogencompound, e.g., N-chlorosuccinimide, N- bromosuccinimide, orN-iodosuccinimide, and an inert diluent, for example, carbontetrachloride, are mixed and heated in the range about 50 to about 100C.

The desired 2,4-di'amino-5-halo-6-phenoxypyrimidines of Formula XX canbe isolated from a halogenation reaction mixture by conventional me hds, fo ex p y Lil evaporation of the diluent, and the product can bepurified, if desired, by conventional methods, for example, byrecrystallization from a suitable solvent or mixture of solvents, or bychromatography.

Oxidation of the Formula XX 2,4-diamino-5-halo-6- phenoxypyrimidine witha percarboxylic acid to produce a Formula XXI1,2-dihydro-1-hydroxy-5-halo-6-phenoxypyrimidine is carried out in thesame manner described above for the percarboxylic acid oxidation ofFormula VII 2,4-diamino-6-phenoxypyrimidines to Formula VI 1,2-dihydro-1-hydroxy-4-phenoxypyrimidines.

The displacement of phenoxy moieties in Formula XV 1,2 dihydro1-hydroxy-5-nitro-4-phenoxypyrimidines, Formula XVIl,Z-dihydro-1-hydroxy-5-nitroso-4-phenoxypyrimidines, Formula XVIII 1,2dihydro 1 hydroxy-5- amino-4-phenoxypyrimidincs, and Formula XXI1,2-dihydro-l-hydroxy-S-halo 4 phenoxypyrimidines with primary andsecondary amines of the formula R H, wherein R is as defined above, iscarried out as described above for the displacement of phenoxy moietiesfrom Formula VI 1,2-dihydro l hydroxy 4 phenoxypyrimidines with primaryand secondary amines of the same formula R H, and the resulting productsare isolated and purified in the manner also described above. Thedisplacement of phenoxy in Formula XXI compounds is especially rapid andcan be carried out in the range about 0 to 100 C., preferably about 20to about 50 C.

The reaction between a Formula XXII1,2-dihydro-lhydroxy-5-halopyrimidine and a thiophenol of Formula XXIIIto produce a Formula XXIV 1,2-dihydro-l-hydroxy-S-arylthiopyrimidine isadvantageously carried out by heating a mixture of those two reactantsin the presence of a strong base, preferably an alkali metal hydroxidesuch as sodium hydroxide or potassium hydroxide, in the range about 50to about 200 C., preferably in the range about to about 125 C., untilthe desired displacement of halogen takes place. For this displacement,it is preferred that the displaced halogen be bromine, i.e., that Y inFormula XXII be bromine. It is also preferred that an excess of theFormula XXIII thiophenol be used, preferably about 2 to about 10 or evenmore molecular equivalents of thiophenol per molecular equivalent of thepyrimidine reactant. It is also preferred that about one molecularequivalent of the strong base be used per molecular equivalent of thepyrimidine reactant. A reaction time of about 1 to about 10 hours isusually required in the preferred temperature range. It is usuallyadvantageous to add a small amount of water, preferably about 5 to about25 percent by weight of the base used, to aid in forming a homogeneousreaction mixture. An inert diluent of appropriate boiling point can alsobe added for that purpose.

The desired Formula XXIV 1,2-dihydro-1-hydroxy-5- arylthiopyrimidine canbe isolated from the reaction mixture by diluting said mixture withwater containing enough alkali metal hydroxide to dissolve the excessthiophenol. The remaining desired product is usually a solid which canbe separated by conventional methods, for example, by filtration,centrifugation, or extraction, and can usually be purified, if desired,by recrystallization from a suitable solvent or mixture of solvents.

The reaction between a Formula XXII 1,2-dihydro-1-hydroxy-S-halopyrimidine and a primary or secondary amine of the formulaR -H to produce a Formula IV 1,2-dihydro-1-hydroxy-5-substituted-aminopyrimidine is advantageouslycarried out by heating a mixture of those two reactants in the rangeabout to about 150 C., preferably in the range about to about C. Thereaction conditions and manipulations are otherwise similar to theabove-described displacement of the phenoxy moiety of a Formula VI1,2-dihydro-1-hydroxy-4-phenoxypyrimidine with an amine of the formula RH. At least one molecular equivalent of the displacing amine should beused. Preferably about 2 to about 10 molecular equivalents is used sothat the excess amine acts as a diluent which results in a homogeneousreaction mixture. Although any of the halogens within the scope ofFormula XXII can be displaced with an amine, it is preferred that thedisplaced halogen be bromine.

Examples of suitable amines for this halogen displacement are thoselisted above as suitable for the phenoxy displacement. A closed reactionvessel is preferred when using those amines whose boiling point atatmospheric pressure is lower than the desired reaction temperature.

The desired Formula IV1,2-dihydro-1-hydroxy-5-substituted-aminopyrimidine can be isolated fromthe reaction mixture by evaporating excess amine and diluent, if one isused, followed by treatment with dilute aqueous base to transform anyamine salts to the free base form. The crude amine product is thenpurified by distillation at reduced pressure, recrystallization from asuitable solvent or mixture of solvents, or chromatography, or by acombination of those methods.

The 1,Z-dihydro-l-hydroxypyrimidines of Formulas I, II, III, and IV aretransformed to monoacid and diacid addition salts by neutralization withappropriate amounts of the corresponding inorganic or organic acid,examples of which are given above. These transformations can be carriedout by a variety of procedures known to the art to be generally usefulfor the preparation of amine acid addition salts. The choice of the mostsuitable procedure will depend on a variety of factors includingconvenience of operation, economic considerations, and particularly thesolubility characteristics of the Formula I, II, III, or IV amine, theacid, and the acid addition salt. If the acid is soluble in water, thebasic compound of Formula I, II, III, or IV can be dissolved in watercontaining either one or two equivalent amounts of the acid, andthereafter, the Water can be removed by evaporation. If the acid issoluble in a relatively non-polar solvent, for example, diethyl ether ordiisopropyl ether, separate solutions of the acid and the basic FormulaI, II, III, or IV compound in such a solvent can be mixed in equivalentamounts, whereupon the acid addition salt will usually precipitatebecause of its relatively low solubility in the non-polar solvent.Alternatively, the basic Formula I, II, III, or IV compound can be mixedwith the acid in the presence of a solvent of moderate polarity, forexample, a lower alkanol, a lower alkanone, or a lower alkyl ester of alower alkanoic acid. Examples of these solvents are ethanol, acetone,and ethyl acetate, respectively. Subsequent admixture of the resultingsolution of acid addition salt with a solvent of relatively lowpolarity, for example, diethyl ether or hexane, will usually causeprecipitation of the acid addition salt. Either monoacid or diacid saltscan be formed by using one or two equivalents, respectively, of theacid.

Acid addition salts of the Formula I, II, III, or IV pyrimidines can betransformed to other acid addition salts by a metathetical exchange ofthe original acid addition salt anion, e.g., the chloride ion, withanother anion, for example, as described above with regard to theformation of penicillin salts.

The carboxyacylates of Formula V are produced by mixing a Formula I, II,III, or IV 1,2-dihydro-1-hydroxypyrimidine with the appropriate amountof a carboxyacylating agent, preferably in the presence of a diluent.

Although substantially any carboxyacylating agent can he used to producethese carboxyacylates, especially suitable are the anhydrides, mixedanhydrides, and acid chlorides of alkanoic, cycloalkanoic, alkenoic,cycloalkenoic, aralkanoic, aromatic, and heterocyclic carboxylic acid.These anhydrides and acid chlorides can also be substituted on anycarbon but the carbonyl carbon with any of a wide variety of atomic ormolecular moieties unreactive with the dihydropyrimidine reactants.Examples of such substituents are alkyl, e.g, methyl, butyl, decyl;alkoxy, e.g., methoxy, ethoxy, pentyloxy; alkylthio, e.g, methylthio,propylthio, heptylthio; dialkylamino, e.g, di-

methylamino, diethylarnino, dihexylarnino; alkoxycarbonyl, e.g.,methoxycarbonyl, propoxycarbonyl, nonoxycarbonyl; carboxyacyl, e.g,acetyl, butyryl; carboxamido, e.g, benzamido, acetamido; nitro; fiuoro;cyano; and the like. Chlorine, bromine, and iodine can also besubstituents on aromatic portions of the carboxyacylating agents.

Examples of suitable anhydrides are acetic anhydride, propionicanhydride, butyric anhydride, isobutyric anhydride, acrylic anhydride,crotonic anhydride, cyclohexanecarboxylic anhydride, benzoic anhydride,naphthoio anhydride, furoic anhydride, and the like, as well as thecorresponding anhydrides substituted with one or more of theabove-mentioned substituents. Examples of suitable acid chlorides areacetyl chloride, propionyl chloride, butyryl chloride, isobutyrylchloride, decanoyl chloride, acryloyl chloride, crotonyl chloride,cyclohexanecarbonyl chloride, 3-cyclohexenecarbonyl chloride,phenylacetyl chloride, succinyl chloride, benzoyl chloride, naphthoylchloride; furoyl chloride, 3-pyridinecarbonyl chloride, phthaloylchloride, and the like, as well as the corresponding acid chloridessubstituted with one or more of the above-mentioned substituents.

At least one molecular equivalent of carboxyacylating agent should beused for the introduction of each carboxyacyl moiety. When reactivecarboxyacylating agents such as acetic anhydride are used, a diacylcompound is usually obtained even with only one molecular equivalent ofcarboxyacylating agent. In such cases, part of the dihydropyrimidinereactant does not form a carboxyacylate.

The carboxyacylation usually takes place rapidly in the range about 20to about +50 C. Suitable diluents are ethers, e.g., diethyl ether andtetrahydrofuran; ketones, e.g., acetone and methyl ethyl ketone; esters,e.g., methyl acetate and ethyl acetate; acetonitrile; pyridine; and thelike. The desired carboxyacylate often separates from the reactionmixture in crystalline form, and can be separated in the usual manner,for example, by filtration or centrifugation. Alternatively, the diluentcan be evaporated, preferably at reduced p essure. The carboxya-cylatescan be purified by conventional techniques, for example, byrecrystallization from a suitable solvent or mixture of solvents.

The nature of each carboxyacylate depends on such factors as the natureof the dihydropyrimidine reactant, the nature and amount ofcarboxyacylating agent, the reaction time, and the reaction temperature.Usually a monoacylate or a diacylate, or a mixture of those, isobtained, although the formation of a triacylate is observed in someinstances. The monoacylatcs are usually N-acyl compounds. The diacylatesare either N,Ndiacyl or O,N- diacyl compounds. Use of the more reactiveacylating agents, cg, acetic anhydride, often results in N,N-diacylates.The less reactive agents, e.g., benzoic anhydride, usually giveN-acylates and/ or O,N-diacylates.

Carboxyacylates produced at relatively low temperatures, i.e., about 20to about 0 C. and with relatively short reaction times, i.e., a fewseconds to about 10 minutes, usually contain larger amounts ofN-monoacylate and O,N-diacylate, and less N,N-diacylate, than thoseproduced at higher temperatures, i.e., about 10 C. to about 50 C. andwith longer reaction times, i.e., about 30 minutes to 100 hours.

Dihydropyrimidine carboxyacylates prepared as described above are easilytransformed back to the Formula I, II, III, or IV dihydropyrimidine freebase, preferably by Warming with a lower alkanol, e.g., methanol orethanol. Simultaneous treatment with a base, for example, gaseousammonia, or an acid, for example, hydrochloric acid, usually acceleratesthe alcoholysis.

As mentioned above, the novel compounds of this invention, i.e.,compounds of Formulas I, II, III, IV, V, and VI, including the freebases and acid addition salts thereof, are useful as antihypertensiveagents, antifertility agents, antiviral agents, antiinfiammatory agents,and as central nervous system stimulants in the treatment of birds andmammals, including man. For those purposes, especially asantihypertensive agents, said novel compounds can be used in thenonprotonated (free base) form or in the protonated (acid addition salt)form either in association with a pharmaceutical carrier in solid orliquid dosage forms, such as tablets, capsules, powders, pills,granules, syrups, elixirs, suppositories, sterile aqueous or vegetableoil dispersions for parenteral use, and the like, alone or incombination with other drugs, for example, in combination withdiuretics, sympathetic blocking agents, ganglion-blocking agents,peripheral vasodilators, reserpinoids, tranquilizers, sedatives, musclerelaxants, antihistamines and other antihypertensives.

Powders are prepared by comminuting the active ingredient to a suitablefine size and mixing with a similarly comminuted diluent. The diluentcan be an edible carbohydrate material such as starch. Advantageously, asweetening agent is present as well as a flavoring agent.

Capsules are produced by preparing a powder mixture as hereinbeforedescribed and filling into formed gelatin sheets. Advantageously, as anadjuvant to the filling operation, a lubricant such as talc, magnesiumstearate and calcium stearate is added to the powder mixture before thefilling operation.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing the active ingredient suitably comminuted, with adiluent or base such as starch, lactose, kaolin, dicalcium phosphate,calcium sulfate, and the like. The powder mixture can be granulated byWetting with a binder such as syrup, gelatin solution, methylcellulosesolution or acacia mucilage and forcing through a screen. As analternative to wet granulating, the powder mixture can be slugged, i.e.,run through a tablet machine and the resulting large tablets broken downinto granules. The granules are further lubricated to prevent stickingto the tablet-forming dies by means of the addition of stearic acid, astearate salt, talc, or mineral oil. The lubricated mixture is thencompressed into tablets.

Advantageously, the tablet can be provided with a protective coatingconsisting of a sealing coat of shellac, a coating of sugar andmethylcellulose, and a polish coating of carnauba Wax.

Oral fluids are prepared in unit dosage forms such as syrups and elixirswherein each teaspoonful of composition contains a predetermined amountof active ingredient for administration.

A syrup is prepared by dispersing the active ingredient in a suitablyflavored aqueous sucrose solution. Similarly an elixir is preparedutilizing an aqueous-alcoholic vehicle. Elixirs are advantageousvehicles for use when a therapeutic agent, which is not suflicientlywater-soluble, is in the composition.

For parenteral administration aqueous fluid unit dosage forms can beprepared. In preparing the parenteral form, a measured amount of activeingredient is placed in a vial, and the vial and its contents aresterilized and sealed. An accompanying vial of sterile water forinjection is provided as a vehicle to form a dispersion prior toadministration. Advantageously, the sterile Water can have dissolvedtherein a local anesthetic and buffering agent. Parenteral aqueoussolutions can also be made by utilizing a pharmacologically acceptablesalt of the active ingredient, such as those mentioned above.

Alternatively, a parenteral suspension can be prepared by suspending theactive ingredient in a parenterally acceptable vegetable oil with orwithout additional adjuvants, and sterilizing after filling into vials.

For veterinary oral use the active ingredient is conveniently preparedin the form of a food premix. The food premix can comprise the activeingredient in admixture with an edible pharmaceutical diluent such asstarch, oatmeal, flour, calcium carbonate, talc, dried fish meal, andthe like. The prepared premix is then conveniently added to the regularfeed, thereby providing medication to the animal in the course offeeding.

The term unit dosage form as used in the specification and claims refersto physically discrete units suitable as unitary dosages for humansubjects and animals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle. The specifications for the novel unit dosage forms of thisinvention are dictated by and directly dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffect to be achieved, and (b) the limitations inherent in the art ofcompounding such active material for therapeutic use in humans andanimals, as disclosed in detail in the specification, these beingfeatures of the present invention. Examples of suitable unit dosageforms in accord with this invention are tablets, capsules, pills, powderpackets, granules, wafers, cachets, suppositories, segregated multiplesof any of the foregoing, and other forms as herein described.

The amount of active ingredient that is to be administered depends onthe age, weight of the patient, the particular condition to be treated,the frequency of administration, and the route of administration. Thedose range is from about 0.1 to about 30 mg. per kg. of body weight,preferably about 0.3 to about 10 mg. per kg. of body weight. The humandose ranges from about to about 500 mg. daily given as a single dose orin 3 or 4 divided doses; preferably, the adult dose is from 25 to about200 mg. Veterinary dosages will correspond to human dosages with amountsadministered being in proportion to the weight of the animal as comparedto adult humans.

The active ingredient is compounded with a suitable pharmaceuticaldiluent in unit dosage form, either alone or in combination with otheractive ingredients. The amount of such other active ingredients is to bedetermined with reference to the usual dosage of each such ingredient.Thus the novel compounds of the invention can be combined with otherhypotensive agents such as onmethyldopa 100-250 mg; with diuretics suchas aminophylline 100-200 mg, bendroflumethiazide 2.5-5 mg.,hydrochlorothiazide -50 mg., trichlormethiazide 2-4 mg., triamterene25-100 mg, ethoxzolamide 50-250 mg., amisometradine 200-400 mg,spironolactone 25-100 mg; sympathetic blocking agents such asguanethidine sulfate 10-50 mg, bethanidine sulfate 5-20 mg;ganglion-blocking agents such as pentolinium bitartrate -200 mg.,mecamylamine hydrochloride 2.5-5 mg., hexamethoniu-m chloride 125-250mg., chlorisondamine chloride -100 mg; peripheral vasodilators such ashydralazine 10-100 mg, beta-pyridyl carbinol -150 mg, mebutamate 300 mg;reserpine type drugs such as reserpine 0.1-l mg., alseroxylon 2-4 mg.,syrosingopine 0.5-2 mg., deserpidine 0.1-1 mg; tranquilizers such asmeprobamate 200- 400 mg, ectylurea 100-300 mg, chlordiazepoxidehydrochloride 5-20 mg., promazine hydrochloride 25-150 mg., diazepan2-10 mg.; sedatives such as phenobarbital 8-60 mg, methyprylon 50-100mg., amobarbital 20-40 mg, ethchlorvynol 100-200 mg.; muscle relaxantssuch as papaverine hydrochloride 20-100 mg., carisoprodol 200- 400 mg,phenaglycodol 200-400 mg.

The invention can be more fully understood by the following examples.

Example 1.2,4-dl'amin0-6-(2,4-dichlor0phen0xy) pyrimidine A mixture of2,4-diamino-6-chloropyrimidine (28.6 g.), potassium hydroxide (13.2 g.of 85%), and 2,4-dichlorophenol ('163 g.) was heated at 150 C. for 3hours. The resulting mixture was cooled to C., and then mixed with asolution of potassium hydroxide (60 g.) in 1000 ml. of water. Aftergradual cooling to 25 C., the mixture was filtered, and the filter cakewas washed thorough- 25 ly with water, and then dissolved in ethanol.The ethanol solution was boiled with decolorizing carbon (Nuchar ISO-N)and then filtered. The filtrate was heated to boiling and diluted withenough water to give 35% aqueous ethanol. After cooling externally withice for hours, the mixture was filtered to give 31 g. of a solid whichwas recrystallized from acetonitrile to give 21 g. of 2,4-diamino 6(2,4-dichlorophenoxy)pyrimidine; M.P. 187- 188 C.

Analysis.Calcd. for C H CI N O: C, 44.30; H, 2.97; N, 20.67, 0, 5.90;CI, 26.15. Found: C, 45.12; H, 3.93; N, 20.12; 0, 4.39; Cl, 25.96.

(C H OH) sh 226 m (e=16,680); 269 m (e=9,680). (0.01 N H SO sh 224 m(e=16,610'); 284 my.

(e=16,610). (0.01 N KOH) sh 226 m .(e=17,900);

(e=10,390). I.R.: (principal bands; mineral oil mull) 3480, 3370, 3300,3140, 1670, 1625, 1545, 1570, 1230, 1195, 1100, 1050, 1010, 795, 755cm."

Example 2.24-diamin.o-6-(2,4-dichl0r0phen0xy) pyrimidine2,4-dichlorophenol (244 g.) was melted and mixed with potassiumhydroxide (28 g. of 85%). The mixture was heated at 110 for minutes todiamino-6-chloropyrimidine (90 g.) was then added grad ually withstirring, and the resulting mixture was heated to 165 C. and maintainedin the range 165 to 170'" C. for 3.5 hours. The reaction mixture wasthen cooled to 110 C. and mixed with a solution of potassium hydroxide(62 g.) in 2000 ml. of water. The resulting mixture was stirred for 15minutes and then cooled slowly to 30 C. during 2 hours. Filtration gavea solid which was thoroughly washed with water and air dried. The driedsolid was dissolved in 1000 ml. of ethanol, and the solution wasrefluxed minutes with decolorizing carbon (Nuchar 190-N) and filtered.The solution was then mixed with an equal volume of water and allowed tostand at about C. for 15 hours. The resulting solid was filtered to give61 g. of 2,4-diamino-6-(2,4-dichlorophenoxy)pyrimidine; M.P. 187-188 C.

Example 3.-2,4-diamin0-6- (2,4,6-trichlar0phen0xy) pyrimidine A mixtureof 2,4-diamino-6-chloropyrimidine .(57.2 g.), potassium hydroxide (264g. of 85%), and 2,4,6-trichlorophenol (236 g.) was heated at 155 C. for3 hours. The resulting mixture was cooled to 100 C., and then mixed witha solution of potassium hydroxide (56 g.) in 2000 ml. of water. Aftergradual cooling to 25 C., the mixture was filtered, and the filter cakewas washed six times with 250-ml. portions of water, and then dissolvedin 800 ml. of ethanol. The solution was boiled with decolorizing carbon(Nuchar 190-N) and filtered. The filtrate was diluted with an equalvolume of water. Cooling and filtration gave 66.9 g. of2,4-diamino-6-(2,4,6-trichlorophenoxy)pyrimidine; M.P. 163-165 C.

Analysis.Calcd. for C H Cl N O: C, 39.31; H, 2.31; N, 18.34; 0, 5.24;CI, 34.81. Found: C, 39.41; H, 2.28; N, 17.96; 0, 4.10; CI, 34.37.

(C H OH) sh 226 m (e=20,300); 269 my (6: 10,200). (0.01 N H 50 226 m(e=20,950); 285 m e=18,150). (0.01 N KOH) 226 m .(e=20,950); 269 mp.

I.R.: (principal bands; mineral oil mull) 3500, 3390, 3340, 3170, 3130',1650, 1615, 1590, 1565, 1240, 1175, 1140, 1050, 86 5, 860, 855'cm.

remove water. 2,4-

Following the procedure of Example 1 but using in place of the2,4-dichlorophenol, phenol; p-chlorophenol; p-bromophenol;2,4-dibromophenol; and m-fiuorophenol, there are obtained2,4-diamino-6-phenoxypyrimidine; 2,4- diamino 6 (p-chlorophenoxy)pyrimidine; 2,4-diamino- 6-(p-bromophenoxy)pyrimidine; 2,4-diamino6-(2,4-dibromophenoxy)pyrimide; and 2,4-diamino6-(m-fiuorophenoxy)pyrimidine, respectively.

Also following the procedure of Example 1 but using in place of the2,4-diamino-6-chloropyrimidine, 2,4-diamino-6-chloro-S-methylpyrimidine; 2,4-diamino-5-butyl-6-chloropyrimidine;2,4-diamino-6 chloro-5-isooctylpyrimidine;2,4-diamino-5-allyl-6-chloropyrimidine;2,4-diamino-6-chloro-5-cro.tylpyrimidine; 2,4-diamino-6-chloro-5-(2-hexenyl pyrimidine;2,4-diamino-6-chloro-5-(2-methoxyethyl)pyrimidine;2,4-diamino-6-chloro-S-cyclopentylpyrimidine;2,4-diamino-6-chloro-5-(4-tert-butylcyclohexyl) pyrimidine;2,4-diamino-6-chloro-S-phenylpyrimidine;2,4-diamino-6-chloro-5-(p-tolyl)pyrimidine; 2,4-diamino-6-chloro-5-(p-tert-butylphenyl) pyrimidine;2,4-(iiamino-S-benzyl-6-chloropyrimidine;2,4-diamino-6-chloro-5-.(4-phenylbutyl)primidine; 2,4-diamino-6-chloro-5o--methylbenzyl pyrimidine;2,4-diamino-6-chloro-5-(4-methyl-1-naphthylmethyl) pyrimidine;

2,4-diamino-6-chloro-5-(m-methoxybenzyl(pyrimidine;

and 2,4-diamino-6-chloro-5-( p-bromobenzyl) pyrimidine,

there are obtained 2,4-diamino-6- 2,4-dichlorophenoxy)-5-methylpyrimidine;

2,4-diamino-5-butyl-6- (2,4-dichlorophenoxy) pyrimidine;

2,4-diamino-6- (2,4-dichlorophenoxy) -5-isooctylpyrimidine;

2,4-diamino-5-allyl-6- 2,4-dichlorophenoxy pyrimidine;

2,4-diamino-6-(2,4-dichlorophenoxy)-5-crotylpyrimidine;

2,4-diamino-6- (2,4-dichlorophenoxy) -5- 2-hexenyl) pyrimidine;

2,4-diamino-6-.( 2,4-dichlorophenoxy) -5- (2-methoxyethyl) pyrimidine;

2,4-diamino-6-(2,4-dichlorophenoxy)-5-cyclopentylpyrimidine;

2,4-diamino-6-(2,4-dichlorophenoxy)-5-(4-tert-butylcyclohexylpyrimidine;

2,4-diamino-6- (2,4-dichlorophenoxy) -5-phenylpyrimidine;

2,4-diamino-6- 2,4-dichlorophenoxy) -5- (p-tolyl) pyrimidine;

2,4-diamino-6-(2,4-dichlorophenoxy)-5-(p-tert-butylphenyl) pyrimidine;

2,4-diamino-5-benzyl-6-(2,4-dichlorophenoxy) pyrimidine;

2,4-diamino-6-(2,4-dichlorophenoxy)-5=(4-phenylbu tyl pyrimidine;2,4-diamino-6 (2,4-dichlorophenoxy)-5-(o-methylbenzyl pyrimidine;2,4-diamino-6-(2,4-dichlorophenoxy)-5-(4-methyl-1-naphthylmethyl)pyrimidine;

2,4-diamino-6-(2,4-dichlorophenoxy)-5-(m-methoxybenzyl) pyrimidine;

and 2,4-diamino-6-(2,4-dichlorophenoxy)-5-(p-bromobenzyl)pyrimidine,

respectively.

Also following the procedure of Example 1 but using in place of thecombination of the 2,4 diamino 6- chloropyrimidine and the 2,4dichlorophenol, each of the specific2,4-diamino-5-substituted-6-chloropyrimidines mentioned above and eachof the specific halophenols mentioned above, there are obtained thecorresponding 2,4 diamino 5 substituted 6 phenoxypyrimidines and 2,4diamino 5 substituted 6 halophenoxypyrimidines. Also following theprocedure of Example 1 but using in place of the 2,4 diamino 6chloropyrirnidine, :a 2,4 diarnino 6 chloropyri-rnidine substituted atthe 5 position separately with each of the specific examples of Rmentioned above, i.e., each of the specific examples of lower alkyl,lower alkenyl, lower alkoxy alkyl, lower cycloalkyl, lower aryl, loweraralkyl, lower alkaryl, lower alkaralkyl, lower alkoxyaralkyl, and lowerhaloaralkyl, there are obtained the corresponding 2,4 diamino 5substituted 6 (2,4-

dichlorophenoxy)pyrimidines. Also following the procedure of Example 1but using in place of the combination of the 2,4 diamino 6chloropyrimidine and the 2,4 dichlorophenol, a 2,4 diamino 6chloropyrimidine substituted at the 5 position separately with each ofthe specific examples of R mentioned above and, separately, phenol andeach of the specific halophenols mentioned above, there are obtained thecorresponding 2,4 diamino 5 substituted 6 phenoxypyrimidines and 2,4diamino 5 substituted 6 halophenoxypyrimidines.

Example 4.-6 amino 4 (2,4 dichlr0phen0xy)-1,Z-dilzydro-1-hydr0xy-2-iminopyrimidine A mixture of 2,4 diamino 6 (2,4dichlorophenoxy)pyrimidine (13.5 g.) and 200 ml. of ethanol was heateduntil a clear solution was obtained. That solution was then cooledrapidly to 0 C., and to the cold solution m chloroperbenzoic acid (11.9g.) was added gradually during 2 hours, keeping the mixture below C. byexternal cooling with ice. The resulting reaction mixture was thenstirred for an additional 4 hours and filtered. The filtrate was mixedwith a solution of potassium hydroxide (60 g. of 85%) in 800 ml. ofwater, and was cooled to 0 C. and maintained there for 1.5 hours. Thesolid which formed was filtered and recrystallized from acetonitrile togive 3.1 g. of 6- amino 4 (2,4 dic-hlorophenoxy) 1,2 dihydro 1- hydroxy2 iminopyrimidine; M.P. 191-193 C.

(ethanol) 226 m (E=4l,600); 278 m (e=6390).

(0.01 N H 80 sh 226 m (e=14,280); 280 m (0.1 N KOH) 226 m (e=41,100);278 m (5:6,-

I.R.: (principal bands; mineral oil mull) 3400, 3340, 3300, 3220, 3200,1640, 1655, 1615, 1595, 1555, 1475, 1210, 1100, 1060, 1000, 790 crnfAddition of absolute ethanol containing one equivalent of hydrogenchloride to an absolute ethanol solution of 6 amino 4 (2,4dichlorophenoxy) 1,2 dihydro 1 hydroxy 2 i-rninopyrimidine, followed byaddition of about 4 volumes of diethyl ether, gives the corresponding1,2 dihydro 1 hydroxypyrimidine monohydrochloride. Similar separate useof benzoic acid, lactic acid, maleic acid, phosphoric acid, sulfuricacid, and succinic acid gives the corresponding 1,2 dihydro 1hydroxypyrimidine acid addition salts. Example 5.6 amino 4 (2,4dichlorophenoay) 1,Z-dihydra-l-hydroxy-Z-il1tinopyrimidine A mixture of2,4 dia-rnino 6 (2,4 diehlorophenoxy)pyrimidine (54.2 g.) and 500 ml. ofethanol (3A denatured) was heated until a clear solution was obtained.Ethylene glycol (300 ml.) was then added, and the mixture was cooled to0 C. To the cold solution, In chloroperbenzoic acid (69.2 g.) was addedgradually during 1.5 hours, keeping the mixture in the range 0 to 10 C.during the addition. The resulting mixture was stirred for 4 hours inthe range 0 to 10 C., and was then filtered into a solution of potassiumhydroxide (25 g. of 85%) in 4000 ml. of water. The resulting combinedfiltrate and solution was allowed to stand for 4 hours at about 25 C.,and was then filtered to give a solid which was washed with water andair dried. The

dried solid was dissolved in 1500 ml. of boiling acetonitrile. Thatsolution was filtered and cooled to 25 C. The resulting solid wasfiltered to give 10.6 g. of 6- amino 4 (2,4 dichlorophenoxy) 1,2 dihydro1- hydroxy 2 iminopyrimidine; M.P. 191-193 C.

Example 6. 6 amino 4 (2,4 dichl0r0phen0xy)- 1,2 dihydro 1 hydroxy 2iminopyrimidine A mixture of 2,4 diamino 6 (2,4dichlorophenoxy)pyrimidine (54.2 g.) and 500 ml. of methanol was heateduntil a clear solution was obtained. That solution was cooled to 0 C.,and m chloroperbenzoic acid (69.2 g.) was added in small portions during1.5 hours, keeping the mixture at about 5 C., and adding an equivalentamount of sodium methoxide in methanol (25% solution) after each suchaddition. The resulting mixture was stirred for 1.5 hours and filtered.The solid filter cake was washed with ml. of methanol, and the combinedfiltrate and washings were concentrated by evaporation under reducedpressure to 300 ml. That solution was mixed with 1500 ml. of water, andthe mixture was cooled at 5 C. for 3 hours. The solid which formed wasfiltered to give 22.6 g. of 6 amino 4- (2,4 dichlorophenoxy) 1,2 dihydro1 hydroxy- 2 iminopyrirnidine; M.P. 191-193 C.

Example 7.6 amino 4 (2,4 dichl0r0phen0xy)-1,Z-dihya'ro-I-hydr0xy-2-imin0pyrimidine A mixture of 2,4 diarnino 6(2,4 dichlorophenoxy)pyrimidine (54.2 g.) and 450 ml. of methanol washeated until a clear solution was obtained. That solution was cooled to0 C., and m chloroperbenzoic acid (19.0 g.) was added gradually during10 minutes, keeping the mixture below 15 C. during the addition. Theresulting mixture was then stirred for 1.25 hours, and then filteredinto a solution of potassium hydroxide (10.0 g.) in 1200 ml. of water.The filter cake (A) was washed with 100 ml. of methanol. The combinedfiltrate, washing, and potassium hydroxide solution was cooledexternally with ice for 3 hours, and was then filtered. The filter cakewas air dried and recrystallized from 800 ml. of acetonitrile to give 14g. of 6 amino- 4 (2,4 dichlorophenoxy) 1,2 dihydro 1 hydroxy- 2iminopyrimidine. Concentration of the acetonitrile mother liquor andcooling gave an additional 3.4 g. of the same product.

The filter cake designated (A), above, was slurried with a solution ofpotassium hydroxide (10.0 g.) in 1500 ml. of water. The slurry wasfiltered to give 28.4 g. of unreacted 2,4 diamino 6 (2,4dichlorophenoxy) pyrimidine.

Example 8.--6-ami:z0-I ,Z-dihydro-l-hydr0xy-2-imino-4-(2,4,6-trichl0rophenoxy) pyrimidine A mixture of2,4-diamino-6-(2,4,6-trichlorophenoxy)- pyrimidine (61.0 g.), ethanol(400 ml.), and ethylene glycol (300 ml.) was cooled to 0 C. To thatmixture, m-ehloroperbenzoic acid (69.2 g.) was added in small portionsduring one hour, keeping the mixture in the range 0 to 5 C. Theresulting mixture was stirred for 5 hours, and then was filtered into asolution of potassium hydroxide (22.4 g.) in 4000 ml. of water. Theresulting combined filtrate and solution was allowed to stand for 4hours at about 25 C., and was then filtered to give a solid. That solidwas mixed with 1800 ml. of acetonitrile, and the mixture was refluxedand filtered at the boiling point. The filter cake was again refluxedwith 1800 ml. of acetonitrile, and the mixture was filtered at theboiling point. The resulting filter cake was recrystallized from 50%aqueous ethanol to give 13.5 g. of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-(2,4,6 trichlorophenoxy)pyrimidine; M.P. 274-275 C.

(ethanol) 226 mu (e=43,250); 278 mp (e=5900). 0.01 N H 50 sh 226 mp.$20,700 278 m 29 0.01 N KOH 226 m (e=48,200); 278 m (e: 6600). LR:(principal bands; mineral oil mull) 3450, 3410, 3220,

820,800 emf.

Following the procedure of Example 6 but using in place of them-chloroperbenzoic acid, in separate experiments, perbenzoic acid;perphthalic acid; peracetic acid; 2,4-dichloroperbenzoic acid;p-methylperbenzoic acid; m-nitroperbenzoic acid, and p-methoxyperbenzoicacid, the same product, 6-amino-4-(2,4-dichlorophenoxy)1,2-dihydrl-hydroxy-Z-iminopyrimidine, is obtained.

Also following the procedure of Example 6 but using in place of the2,4-diamino-6- (2,4-dichlorophenoxy) pyrimidine;2,4-diamino-6-phenoxypyrimidine;

2,4-diamino-6- (p-chloro-phenoxy) pyrimidine; 2,4-diamino-6-(p-bromophenoxy) pyrimidine; 2,4-diamino-6- (2,4-dibromophenoxy)pyrimidine; and 2,4-diamino-6- (m-fluorophenoxy) pyrimidine,

there are obtained6-amin'o-1,2-dihydro.-1-hydroxy-2-imino-4-phenoxypyrimidine;

6-amino-4-(p-chlorophenoxy) -1,2-dihydro-1-hydroxy-2- iminopyrimidine;

6-arnino-4-(p-bromophenoxy) -1,2-dihydro-1-hydroxy-2- iminopyrimidine;

6 -amino-4- (2,4-dibromophenoxy)-1,2-dihydro-1-hydroxy-2-iminopyrimidine; and

6-amino-1,2-dihydro-4- (m-fluorophenoxy) -1-hydroxy-2- iminopyrimidine,respectively.

Also following the procedure of Example 6 but using in place of the2,4-diamino-6-(2,4-dichlorophenoxy)-5-(p-tolyl) pyrimidine;

2,4-diamino-6- (2,4-dichlorophenoxy) (p-tert-butylp'henyl pyrimidine;

2,4-diamino-5-benzyl-6- 2,4-dichlorophenoxy) pyrimidine;

2,4-diamino-6- (2,4-dichlorophenoxy) -5- (4-phenylbutyl) pyrimidine;

2,4-diamino-6- 2,4-dichlorophenoxy) -5- o-methylbenzyl) pyrimidine;

2,4-diamino-6-(2,4-dichlorophenoxy) -5-(4-methyl-1- naphthylmethyl)pyrimidine;

2,4-dia1nino-6- (2,4-dichlorophenoxy -5- (m-methoxybenzyl pyrimidine;and

2,4-diamino-6- (2,4-dichlorophenoxy) -5- (p-bromobenzyl) pyrimidine,

there are obtained6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-imino-5-methylpyrimidine;

6-amino-5-butyl-4-(2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-2-iminopyrimidine;

6-amino-4-(2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-2-imino-5-isooctylpyrimidine;

5-allyl-6-amino-4-(2,4-dichlorophenoxy) -1,2-dihy-dro-1-hydroxy-Z-iminopyrimidine;

6-amino-5-crotyl-4- 2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-2-iminopyrimidine;

6-amino-4- (2,4-dichlorophenoxy) -1,2-dihydro-5- (2-hexenyl)-1-hydroxy-2-iminopyrimidine;

6-amino-4- (2,4-dichlorophenoxy) -1,2-dihydro-1-hydr0xy- 2-imino-5(Z-methoxyethyl) pyrimidine;

6-amino-5-cyclopentyl-4- 2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy2-iminopyrimidine;

6-amino-5- 4-tert-butylcyclohexyl -4- (2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-iminopyrimidine;

6-amino-4-(2,4-dichlorophenoxy) -l,2-dihydro-1-hydroxy-2-imino-5-phenylpyrimidine;

6-amino-4-(2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy- 2-imino-5-(p-tolyl) pyrimidine;

6-amino-5- (p-tert-butylphenyl) -4- (2,4-dichlorophenoxy)1,2-dihydro-1-hydroxy-2-iminopyrimidine;

6-amino-5-benzyl-4- (2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-2-imino pyrimidine;

6-amino-4-(2-4-dichlorophenoxy) -1,2-dihydro-1-hydroxy- 2-imino-5-(4-phenylbutyl) pyrimidine;

6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy- 2-imino-5-(o-methylbenzyl) pyrimidine;

6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy- 2-imino-5-(4-methyll-naphthylmethyl) pyrimidine;

6-amino-4- (2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy- 2-imino-5-(m-methoxybenzyl) pyrimidine; and

6-amino-5-(p-bromobenzyl)-4-(2,4-dichlorophenoxy)-1,

Z-dihydro-1-hydroxy-2-iminopyrimidine, respectively.

Following the procedure of Example 4, each of the above-mentionedspecific 1,Z-dihydro-l-hydroxypyrimidines is transformed to thecorresponding hydrochloric acid, benzoic acid, lactic acid, phosphoricacid, sulfuric acid, and succinic acid addition salts.

Also following the procedure of Example 6 but using in place of the2,4-diamino-6-(2,4-dichlorophenoxy)pyrimidine, each of the other2,4-diamino-5-substituted-6- phenoxypyrimidines and each of the other2,4-diamino-5- substituted-6-halophenoxypyrimidines indicated above asprepara'ble by the procedure of Example 1, there are obtained thecorresponding 6-amino-1,2-dihydro-l-hydroxy- 2 imino-4-phenoxy 5substituted-pyrimidines and 6- amino-l,2-dihydro 4 halophenoxy 1hydroxy-2- imino-S-substituted-pyrirnidines Example9.-6-amino-1,2-dihydr0-1-hydroxy-2-imin04- piperidinopyrimidine Amixture of 6-amino 4 (2,4-dichlorophenoxy)- 1,2-dihydro 1 hydroxy 2iminopyrimidine 3.5 g.) and piperidine (20 ml.) was heated in a sealed,heavywall, glass tube in an oil bath at C. for 2.5 hours. The tube andcontents were then cooled slowly to 25 C. The tube was opened and thereaction mixture filtered. The solid was washed first with piperidineand then with diethyl ether, and was dried to give 1.2 g. of6-amino-1,2- di'hydro-l-hydroxy 2 imino 4 piperidinopyrirnidine; M.P.262264 C. with decomposition.

Analysis.-Calcd. for C H N O: C, 51.66; H, 7.22; N, 33.47; 0, 7.65.Found: C, 52.27; H, 7.00; N, 33.34; 0, 7.56.

(Ethanol) 230 m, (e=35,210);261m/L (e=11,210);

285 mp. (e=11,790). (0.01 N n sop 232 In $26,350 280 m (e=23,850). (0.01N KOH) 231 -m,u (e=36,100); 261.5 my

E=11,40o 285 my $12,040 I.R: (principal bands; mineral oil mull) 3450,3420, 3400, 3370, 3260, 1655, 1250, 1230, 1210, 1165, 1020 cmr Additionof absolute ethanol containing one equivalent of hydrogen chloride to anabsolute ethanol solution of 6 amino1,2-dihydro-1-hydroxy-2-amino-4-piperidinopyrimidine, followed byaddition of about 4 volumes of 31 I diethyl ether, gives thecorresponding monohydrochloride. Similar use of 2 equivalents ofhydrogen chloride gives the corresponding dihydrochloride. Similarseparate use of benzoic acid, lactic acid, succinic acid, maleic acid,sulfuric acid, and phosphoric acid gives the corresponding1,2-dihydro-1-hydroxypyrimidine acid addition salts.

Example 10.-6-amin0-1,Z-dihydro-I-hydroxy-2-imin0-4-piperidino-pyrimidine A mixture of6-amino-4-(2,4-dichlorophenoxy)1,2-dihydro-1-hydroxy-Z-iminopyrimidine(22.0 g.) and piperidine (200 ml.) was heated in a sealed, heavy-wall,glass tube in an oil bath up to the range 175l80 C. during 1 hour, andwas held within that range for 4 hours. The tube and contents were thencooled slowly to 25 C. during about 9 hours. The tube was opened and thereaction mixture was filtered. The solid was Washed first with about 15ml. of piperidine and then with diethyl ether to give 12.1 g. of6-amino-l,Z-dihydro-l-hydroxy-Z-imino- 4-piperidinopyrimidine; M.P.262266 with decomposition starting at 262 C.

Following the procedure of Example but using in place of the piperidine,dimethylamine; diethylamine; dibutylamine; N methylbutylamine;N-ethylhexylamine; butylamine; octylamine; diallylamine; dicrotylamine;di- (2-hexenyl)amine; N-methylallylamine; allylamine; 2-0ctenylamine;dibenzylamine; diphenethylamine; N-methylbenzylamine;N-ethyl-(1-naphthylmethyl)amine; benzylamine; 3-phenylpropylamine;cyclohexylamine; dicyclohexylamine; cyclobutylamine;N-methyl-(4-tert-butylcyclohexyl)amine; azctidine; pyrrolidine;2-methylpyrrolidine; 3-ethylpyrrolidine; 2,5-dimethylpyrrolidine; 2-methyl-S-ethyl-piperidine; 3-isopropylpiperidine; 2,4,6-trimethylpiperidine; hexahydroazepine; 4-tert-butylhexahydroazepine;heptamethylenimine; octamethylenimine; morpholine; 2-ethylmorpholine;and N-rnethylpiperazine, there are obtained6-amino-1,2-dihydro-4-dimethylamino-1-hydroxy-2- iminopyrimidine;6-amino-4-diethyl-amino-1,2-dihydr0-1-hydroxy- 2-irninopyrimidine;6-amino-4-dibutylamino-1,2-dihydro-l-hydroxy-2- iminopyrimidine6-amino-1,2-dihydrol-hydroxy-2-imino-4-(N-methylbutylamino pyrimidine;6-amino-1,2-dihydro-4-(N-ethylhexylamino )-1-hydroxy-2-iminopyrimidine;'6-amino-4-butylamino-1,2-dihydro-1-hydroxy-2- iminopyrimidine; 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-octylaminopyrimidine;6-amino-4-diallylarnino-1,2-dihydro1-hydroxy-2- iminopyrimidine;6-amino-4-dicrotylamino-l,2-dihydro-1-hydroxy-2- iminopyrimidine;6-amin0-4- [di- (2-hexenyl) amino] l ,2-dihydro-1-hydroxy-2-iminopyrimidine;6-amino-1,Z-dihydro-1-hydroxy-2-irnino-4-(N-methylallylamino pyrimidine;4-allylamino-6-amino-1,2-dihydro-1-hydroxy-2- iminopyrimidine;6-amino-1,2-dihydro-1-hydroxy-2-imino-4-(2-octenylamino pyrimidine;6-amino-4-dibenzylamino-l,2-dihydro-1-hydroxy-2- iminopyrimidine;6-amino-1,2-dihydro-4-diphenethylamino-l-hydroxy- Z-iminopyrimidine;6-amin0-1,2-dihydr0-1-hydroXy-2-imin0-4-(N-methylbenzylamino pyrimidine;6-amino-1,2-dihydro-4- [N-ethyl-( l-naphthylmethyl)- amino]-1-hydroxy-2-iminopyrimidine;6-amino-4-benzylamino-1,2-dihydro-1-hydroxy-2- iminopyrimidine;6-amino-1,2-dihydro-1-hydroxy-2-imino-4- (3-phenyl propylaminopyrimidine;

32 6-amino-4-cyclohexylamino-1,2-dihydro-1-hydroxy-2- iminopyrimidine;6-amino-4-dicyclohexylamino-1,2-dihydrol-hydroxy-Z- iminopyrimidine;6-amino-4-cyclobutylamino-1,2-dihydro-1-hydroxy-2- iminopyrimidine;6-amino-1,2-dihydro-1-hydroxy-2-imino-4-[N-methyl-(4-tert-butylcyclohexyl) amino] pyrimidine; 6-amino-4-(1-azetidinyl)1,2-dihydro-1-hydroxy-2- iminopyrimidine;6-amino-l,2-dihydro-1-hydroxy-2-imino-4-( l-pyrrolidinyl pyrimidine;6-amino-l,Z-dihydro-l-hydroxy-2-imino-4-[1-(2- methylpyrrolidinyl)]pyrimidine; 6-amino-1,2-dihydro-4-[1-(3-ethylpyrrolidinyl)1-1-hydroxy-2-iminopyrimidine; 6-amino-1,2-dihydro-4- l- (2,5-dimethylpyrrolidinyl) l-hydroxy-Z-iminopyrimidine;6-amino-1,2-dihydro-1-hydroxy-2-imino-4-(2-methyl- S-ethylpiperidinopyrimidine;6-amino-1,2-dihydro-l-hydroxy-2-imino-4-(3-isopropylpiperidinopyrimidine; 6-amino-l,2-dihydro-1-hydroxy-2-imino-4-(2,4,6-

trimethylpiperidino) pyrimidine; 6-amino- 1 ,2-dihydro-4-(l-hexahydroazepinyl) -1- hydroxy-Z-iminopyrimidine; 6-amino-4- 1-(4-tert-butylhexahydroazepinyl) 1,2-dihydro-1-hydroxy-2-iminopyrimidine;6-amino-1,2-dil1ydro-4-1-heptarnethy1enimino)-lhydroxy-2-iminopyrimidine;6-amino-1,2-dihydro-1-hydroxy-2-imino-4-( l-octamethyleniminopyrimidine;6-amino-1,2-dihydro-1-hydroxy-2-imino-4-morpholinopyrimidine;6-amino-1,2-dihydro-4-(2-ethylmorpholino)-1-hydroxy-2- iminopyrimidine;and G-amino-1,2-dihydro-1-hydr0xy-2-imino-4-(4-methyll-piperazinyl)pyrimidine, respectively.

Following the procedure of Example 9, each of the above-mentionedspecific 1,2 dihydro-l-hydroxypyrimidines is transformed to thecorresponding hydrochloric acid, benzoic acid, lactic acid, maleic acid,phosphoric acid, sulfuric acid, and succinic acid addition salts.

Also following the procedure of Example 10 but using in place of thepiperidine, each of the primary and secondary amines corresponding toeach of the specific examples of and heterocyclic moieties Within thescope of R as defined and given above, there are obtained thecorresponding 6 amino-1,2-dihydro-l-hydroxy-2-iminopyrimidines,substituted at the 4-position with a mono-substituted or disubstituted,including heterocyclic, amino moiety.

Also following the procedure of Example 10 but using in place of the6-amino-4- (2,4-dichlorophenoxy) -1,2-dihydro-1- hydroxy-Z-iminopyrimidine; 6-arnino-4-(2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-2-imino-5-methylpyrimidine; 6-amino-5-butyl-4-(2,4-dichlorophenoxy) -l,2-dihydro- 1-hydroxy-2-iminopyrimidine;6-amino-4-(2,4-dichlorophenoxy)-1,Z-dihydro-lhydroxy-Z-imino-5-isooctylpyrimidine;5-allyl-6-amin0-4- (2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-2-iminopyrimidine; 6-amino-5-crotyl-4-(2,4-dicl1lorophenoxy)-1,2-

dihydro-l -hydroxy-2-iminopyrimidine; 6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-5- (Z-hexenyl -1-hydroxy-Z-iminopyrimidine; 6-amino-4-(2,4-dichlorophenoxy)-l,2-dihydro-1- hydroxy-Z-imino-S- (2-methoxyethyl-pyrimidine;

6 -amino-5 -cycl op entyl-4- 2,4-dichlorophenoxy) 1,2-

dihydro-1-hydroxy-2-iminopyrimidine;

6-amino-5- 4-tert-butylcyclohexyl) -4- 2,4-dichlorophenoxy) 1,Z-dihydro-l -hydroxy-2-i.rnino pyrimidine;

6-amino-4-(2,4-dichlorophenoxy)-1,2-dihyd-ro-1-hydroxy-2-iinino-5-phenylpyrimidine;

6-amino-4- (2-,4-dichlorophenoxy) -1,2-dihydro-1- hydroxy-Z-irnin -5(p-tolyl pyrimidine;

6-amino-5- (p-tertbutylphenyl) -4- (2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-iminopyrirnidine;

6-amino-5-benzyl-4- (2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-2-iminopy1 iniidine;

6-amino-4- (2,4-dichlorophenoxy) -1 ,Z-dihy-dro- 1- hydr oxy-2-imino-S-(4-phenylbutyl) pyrimidine;

6-amino-4-(2,4-dichlorophenoxy) -l,2-dihydro-1- hydroxy-Z -imin 0-5(o-rnethylbenzyl pyrimidine;

6-amino-4-(2,4-dichlorophenoxy) -1,2-dihydro-1- hydroxy2-irnino-5-4-methyll-n aphthylmethyl) pyrimidine;

6-amino-4-(2,4-dichlorophenoxy) -1,2-dihydro-1-hydroxy-Z-imino-5-(m-methoxybenzyl)-pyrimidine,

and 6-amino-5- (p-bromobenzyl) -4- (2,4-dichlorophenoxy)-1,Z-dihydro-l-hydroxy-2-iminopyrimidine, there are obtained6-amino-1,Z-dihydro-l-hydroxy- 2-imino-5-methyl-4-piperidinopyrimidine;

G-amino-S-butyl-1,Z-dihydro-l-hydroxy-2-imino-4- piperidin opyrimidine;

6-amino-1,2-dihydro-1-hydroxy-2-imino-5-isooctyl-4-piperidinopyrimidine;

5-allyl-6-amino-1,2-dihydro-l-hydroxy-2-imino-4- piperidinopyrimidine;

6-amino-5-croty1-1,2-dihydro-l-hydroxy-2-imino-4- piperidinopyrimidine;

6-amino-l,2-dihydro-5-(2-hexenyl) -1-hydroxy-2-imino-4-piperidinopyrimidine;

6-amino- 1,2-dihydro- 1 -hydroxy-2-irnino-5- (2- methoxyethyl)-4-piperidinopyrimidine;

6-amino-5-cyclopentyl-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine;

6-amino-5- (4-tert-butylcyclohexyl)-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine;

6-amino-1,Z-dihydro-l-hydroxy-2-imino-5-phenyl-4- piperidinopyrimidine;

6-amino-1,Z-dihydro-l-hydroxy-2-imino-4-piperidino- 5 p-tolyl)pyrimidine;

6-amino-5- (p-tert butylphenyl)-1,2-dihydro-1-hydroxy-Z-imino-4-piperidinopyrimidine;

6-amino-5-benzyl-1,2-dihydro-1-hydroxy-2-imin0-4- piperidino-pyrimidine;

6-arnino-1,Z-dihydro-1-hydroXy-2-imino-5-(4-pheny1- 'butyl-4-piperidinopyrimidine;

6-amino-1,Z-dihydro-1-hydroxy-2-imino-5-(o-methylbenzyl)-4-piperidinopyrimidine;

6-amino-1,2-dihydro-1-hydroxy-2-imino-5-(4-methyll-naphthylmethyl)-4-piperidinopyrimidine;

6-amino-1,2-dil1y-dro-l-hydroxy-Z-imino-S-(mmethoxybenzyl-4-piperidinopyrimidine;

and6-amino-1,2-dihydro-l-hydroxy-Z-imino-S-(pbrornobenzyl)-4-piperidinopyrimidine,respectively.

Following the procedure of Example 9, each of the above-mentionedspecific 1,2-dihydro-l-hydroxypyrimidines is transformed to thecorresponding hydrochloric acid, benzoic acid, lactic acid, maleic acid,phosphoric acid, sulfuric acid, and succinic acid additon salts.

Also following the procedure of Example 10 but using in place of thecombination of the 6-amino-4-(2,4-dichlorophenoxy) 1,2 dihydro 1 hydroxy2 iminopyrimidine and the piperidine, each of the above-mentioned 6amino 1,2 dihydro 1 hydroxy 2 imino- 4-phenoxypyrimidines orG-amino-1,2-dihydro-1-hydroxy- 2-imino-4-halophenoxypyrimidines,unsubstituted or substituted at the 5-position as above-described, andeach of the above-mentioned primary and secondary amines,

there are obtained the corresponding6-amino-1,2-dihydro-l-hydroxy-Z-imino pyrimidines wherein the 4-phenoxyor 4-halophenoxy substituent has been replaced with a mono-substitutedor disubstituted, including heterocyclic, amino moiety.

Example 11 .-6-amin0-1,2-dihydr0-I-hydr0xy-2-imin0- 5 -nitros0-4-piperidin0pyrimidine 6 amino 1,2 dihydro 1 hydroxy 2 imino 4-piperidinopyrimidine (4.5 g.) was rnixed with 25 011. of sulfuric acid,keeping the temperature of the mixture below 40 C. The resultingsolution was cooled to 15 C., and a solution of sodium nitrite (1.4 g.)in 2 ml. of water was added dropwise with stirring, keeping the mixturebelow 20 C. The resulting mixture was stirred for 45 minutes at 15 C.,and was then poured into a mixture of sodium hydroxide (37 g.), crushedice g), and water (200 1111.). That mixture was stirred and neutralizedwith solid sodium carbonate. The solid which formed was filtered, washedwith water, and recrystallized from 75 ml. of ethanol to give 2.1 g. of6-amino1,2-dihydro 1 hydroxy 2 imino 5 nitroso- 4-piperidinopyrimidine;M.P. -1915 C.

Analysis.-Calcd. for C H N O C, 45.37; H, 5.92. Found: C, 45.51; H,5.73.

(ethanol) 219 m;1(e=17,300'); sh 240 my. (e=12,300); 264 m (e=16,150);325 my. (e=12,350).

(0.01 N H 80 242 m (e=22,700); 322 my (0.01 N KOH) 238 m (e=16,350); sh270 mu (e=6900); 347 my (e=12,050).

I.R.: (principal bands; mineral oil mull) 3390, 3200, 3190', 1655, 1615,1560, 1525, 1485, 1340, 1180, 1140, 1125, 1020, 855, 755, 725 cm.

Example 12.6-am in0-4- (2,4-dichlorophenoxy-1,2-dihydro-I-hydr0xy-2-imino-S-nitrosopyrimidine Following theprocedure of Example 11, 6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy 2 iminopyrimidine was mixedwith sulfuric acid and then with sodium nitrite to give6-amino-4-(2,4-dichlorophenoxy)-l,2-dihydro-1-hydroxy-2-imino-5-nitrosopyrimidine.

Addition of absolute ethanol containing one equivalent of hydrogenchloride to an absolute ethanol solution of 6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro 1 hydroxy-2-imino-5-nitrosopyrimidine, followed by addition of about 4 volumes ofdiethyl ether, gives the corresponding hydrochloride.

Following the procedure of Example 12 but using in place of the6-amino-4-(2,4-dichlorophenoxy) 1,2 dihydro-1-hydroxy-2-iminopyrimidine,6-amino 1,2 dihydro-l-hydroxy-2-imino-4 phenoxypyrimidine and each ofthe above-mentioned specific6-amino-l,2-dihydro-1-hydroxy-2-imino-4-halophenoxypyrirnidines,unsubstituted at the 5-position, there are obtained the corresponding 5nitrosopyrimidines.

35 Example 13.6-amin0-1,Z-dihyrlro-I-hya'roxy-2-imirz0-5-nitros0-4-piperidinopyrimidine Following the procedure of Example 10,6-amino-4- (2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy 2 imino-S-nitrosopyrimidine was mixed with piperidine and heated in a sealedglass tube to give 6-amino-1,2-dihydro-1-hydroxy-2-imino-5-nitroso-4piperidinopyrimidine with essentially the same physical propertiesdescribed in Example 11.

Following the procedure of Example 13 but using in place of piperidine,each of the above-mentioned primary and secondary including heterocyclicamines, there are obtained the corresponding 6amino-1,2-dihydro-1-hydroxy-Z-imino-S-nitrosopyrimidines substituted atthe 4- position with a mono-substituted or disubstituted amino moiety,and with essentially the samephysical properties as the compoundsprepared by the alternative route as exemplified in example 11.

Example 14.6-amirzo-1,Z-dihydro-I-hydr0xy-2-imin0-5-nitr0-4-piperidinopyrimidine A solution of6-arnino-1,2-dihydro-1-hydroxy-2-imino- 4-piperidinopyrimidine (3.0 g.)in 10 ml. of 95% sulfuric acid was cooled to 10 C. A mixture of 70%nitric acid (1 ml.) and 95% sulfuric acid (4 ml.) was added dropwisewith stirring during 1.5 hours. The resulting solution was stirred anadditional 30 minutes, and was then poured onto 250 g. of crushed ice.The mixture was mixed first with potassium hydroxide (25.5 g. of 85%)and then with potassium bicarbonate (12.0 g.), keeping the temperatureof the mixture below 20 C. The mixture was then filtered, and the filtercake was washed with water and slurried with 300 ml. of water. Theslurry was filtered and the solid was recrystallized from a mixture ofWater (175 ml.) and ethanol (75 ml.) to give 2.4 g. of6-an1ino-1,2-dihydro-1- hydroxy-2-imino-5-nitro 4 piperidinopyrimidine;M.P. 248-250" C.

Analysis.Calcd. for C H N O C, 42.51; H, 5.55; O, 18.88. Found: C,42.37; H, 5.44; O, 18.75.

(ethanol) 222 mp. (e=2l,000); 270 m (e=20,900);

51 sh 340 m (E=5300); 378 mp. (e=5800).

(0.01NH SO sh 236 mp. (s=1740); 260

(e=26,050); 293 mp (e=6750); 343 (e=7250).

(0.01NKOH) 220 m, (e=20,700); sh 248 (e=15,450); 268 mp. (e=14,550); 378(e=9350).

LR: (principal bands; mineral oil mull) 31-40, 3390, 3150, 1655, 1640,1610, 1565, 1525, 1480, 1265, 1175, 1120, 1020 CH1."'1.

Example 15.6-amin0-4- (2,4-diclzloro-fi-nitrvphenoxy1,2-dihydr-1-hydroxy-Z-in1ino-5-nitr0pyrimidine A solution of6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-iminopyrimidine(3.0 g.) in 10 ml. of 95 sulfuric acid was cooled to 10 C. A mixture of70% nitric acid (1 ml.) and 95% sulfuric acid ml.) was added dropwisewith stirring during 1.5 hours. The resulting mixture was stirred anadditional hour at 20 C.,

and was then poured onto crushed ice. The mixture was stirred and theinner glass walls of the container were rubbed with a glass rod untilthe ice melted. The resulting solid was filtered, washed with water, andextracted with ethanol to give 2.2 g. of6-amino-4-(2,4-dichloro-6-nitrophenoxy)-1,Z-dihydro-l-hydroxy-Z-imino 5nitropyrimidine; M.P. 229230 C.

Analysis.-Calcd. for C H N O CI C, 31.85; H, 1.60; Cl, 18.80. Found: C,32.39;-H, 181; C1, 18.35.

U.V: (ethanol) 218 m (e=36,950); 267 my. (e=14,650);

313 III/L (e=12,600). (0.01 N H 50 217 um (c:36,850);

14,540); 311 mu (e=13,520). 0.01 N KOH) 220 mp. $36,550 269 mp. (6:9,-

425); 369 mp. (e=13,680). I.R: (principal bands; mineral oil mull) 3440,3360, 3320, 3260, 1655, 1640, 1625, 1525, 1510, 1490, 1560, 1365, 1345,1235, 1215, 1140, 1090, 815, 790, 760, 730 cm.-

Example 16.6-amin0-1,Z-dihydro-I-lzydr0xy-2-imin0-5-nitr0-4-piperidinopyrimidine Following the procedure of Example 10,6-amino-4- (2,4-dichloro-6-nitrophenoxy)-1,2-dihydro1-hydroxy 2-imino-S-nitro-pyrimidine was mixed with piperidine and heated in asealed glass tube to give 6-amino-1,2-dihydro- 1-hydroxy-2-imino-S-nitro4 piperidinopyrimidine with essentially the same physical propertiesrecited in Example 14.

U.V: (ethanol) sh 223 m (e=14,670); 240 m (6 17,-

0.01 N KOH) sh 223 m, $15,750 238 m (e=18,540); sh 263 m (e=7130); 317 m(e=7540).

LR: (principal bands; mineral oil mull) 3300, 3160, 2600, 1650, 1620,1545, 1525, 1235, 1205, 1160, 1125, 1020 cmr Addition of an equivalentamount of aqueous sodium hydroxide solution to an aqueous solution of5,6-diamino- 1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidinehydrochloride gives the corresponding free base. That free base isisolated by passing a methanol solution of the hydrochloride over abasic ion exchange resin such as Amberlite IR-400 followed byevaporation of the ether solution under reduced pressure and in theabsence of moisture and oxygen.

Following the procedure of Example 17 but using in place of the6-amino-1,2-dihydro-l-hydroxy-Z imino 5- nitro-4-piperidinopyrimidine,each of the above-mentioned 6-amino-1,Z-dihydro-l-hydroxy-Z-imino 5nitropyrimidines substituted at the 4-position with a mono-substitutedor disubstituted including heterocyclic amino moiety is catalyticallyhydrogenated to give the corresponding 5,6-diamino-1,2-dihydro-1-hydroxy-2-iminopyrimidine hydrochloride,substituted at the 4-position as in the reactant. Each of those5,6-diamino compounds is then transformed to the free base as describedin Example 17.

Example 18.5,6-diamin0-1,Z-dihydro-I-hydr0xy-2imin0-4-piperidinopyrimia'ine Following the procedure of Example 17,6-amino-1,2-

dihydro-l-hydroxy-2-imino-5-nitroso-4 piperidinopyrimi- 37 dine isshaken with hydrogen in the presence of palladium on charcoal to givethe hydrochloride of 5,6-diamino-l,2- dihydro-1-hydroxy-2-imino-4piperidinopyrimidine with essentially the same physical propertiesrecited in Example 17.

Following the procedure of Example 18 but using in place of the6-amino-1,2-dihydro-1-hydroxy-2-imino-5-nitroso-4-piperidinopyrimidine,each of the above-mentioned6-amino-1,2-dihydro-1-hydroxy-2-imino-5-nitrosopyrimidines substitutedat the 4-position with a mono-substituted or disubstituted includingheterocyclic amino moiety is catalytically hydrogenated to give thecorresponding 5,6-diamino-l,2-dihydro-2-iminopyrimidine hydrochloridesubstituted at the 4-position as in the reactant. Each of those5,6-diamino compounds is then transformed to the free base as describedin Example 17. Each hydrochloride and free base has essentially the samephysical properties as the 5,6-diamino compound prepared from thecorresponding S-nitro compound as described above,

Example J9.5,6-diamin'-4-(2,4-dichl0rophenoxy) 1,2-dihydra-l-hydroxy-Z-imin0pyrimidine Following the procedure of Example17, 6-amino-4-(2, 4-dichlorophenoxy)-1,2-dihydro-1-hydroxy-2 iminonitrosopyrimidine is shaken with hydrogen in the presence of palladiumon charcoal to give the hydrochloride of5,6-diamino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1hydroxy-Z-iminopyrimidine. The corresponding free base is obtained byneutralization of said hydrochloride, also as described in Example 17.

Following the procedure of Example 19' but using in place of the6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-imino-5-nitrosopyrimidine,6-amino-l,2- dihydro-1-hydroxy-2-imino-5-nitroso 4 phenoxypyrimidine andeach of the above-mentioned 6-amino-l,2-dihydro-1-hydroxy-2-imino4-halophenoxy 5 nitrosopyrimidines, there are obtained the corresponding5,6-diamino compounds first as hydrochlorides and then as free bases.

Example 20.5,6-diamino-4-(2-amin04,6-dichl0rophenoxy-1,2dihydro-1-hydroxy-2-iminopyrimidine Following the procedure ofExample 17, 6-amino-4-(2, 4-dichlor0-6-nitrophenoxy)-1,2-dihydro 1hydroxy 2- imino-S-nitropyrimidine is shaken with hydrogen in thepresence of palladium on charcoal to give the hydrochloride of5,6-diamino-4-(2-amino-4,6-dichlorophenoxy)-l,2-dihydro-1-hydroxy-Z-iminopyrimidine, The corresponding free base isobtained by neutralization of said hydrochloride, also as described inExample 17.

Following the procedure of Example 20 but using in place of the6-amino-4-(2,4-dichloro-6-nitrophenoxy)- 1,2 dihydro 1hydroxy-2-imino-5-nitropyrimidine, 6- amino 1,2 dihydro 1 hydroxy 2imino-5-nitro-4- phenoxypyrimidine and each of the above-mentioned 6-amino 1,2 dihydro-1-hydroxy-2-imino-4-halophenoxy- 5-nitropyrimidines,there are obtained the corresponding 5,6-diamino compounds, first ashydrochlorides and then as free bases. Those diamino compounds haveessentially the same physical properties as the diamino compoundsprepared from the corresponding nitroso compounds as described above.

Example 21 .5,6-diamino-1,Z-diltydro-I-hydr0xy-2-imino-4-piperidinopyrimidine Following the procedure of Example 10,5,6-diamino- 4 (2,4 dichlorophenoxy) 1,2 dihydro 1-hydroxy-2-iminopyrirnidine was mixed with piperidine and heated in a sealed glasstube to give 5,6-diamino-l,2-dihydro-1- hydroxy 2imino-4-piperidinopyrirnidine hydrochloride with essentially the samephysical properties recited in Example 17. The free base correspondingto this hydrochloride was obtained as described in Example 17.

Following the procedure of Example 21 but using in place of thepiperidine, each of the primary and secondary including heterocyclicamines mentioned above, there are obtained first the hydrochlorides andthen the free bases of the corresponding 5,6-diamino-l,2-dihydro-1-hydroxy-2-iminopyrimidines substituted at the 4-position with amono-substituted or disubstituted amino moiety and with essentially thesame physical properties as the compounds prepared by the alternativeroute as exemplified in Examples 17 and 18.

Example 22 .5-brom0-2,4-diamin0-6- (2,4-dlC/il0l'0- ph enoxy pyrimidineA mixture of 2,4-diamino-6-(2,4-dichlorophenoxy)- pyrimidine (81.3 g),N-bromosuccinimide (53.4 g.), and carbon tetrachloride (600 ml.) wasboiled under reflux for one hour. The resulting reaction mixture wasevaporated to dryness, and the residue was washed with water andfiltered. Recrystallization from methanol gave 5-bromo-2,4-diamino-6-(2,4-dichlorophenoxy)-pyrimidine.

Following the procedure of Example 22 but substituting for theN-bromosuccinimide, N-chlorosuccinirnide and N-iodosuccinimide, thereare obtained the corresponding S-chloro and5-iodo-2,4-diamino-6-(2,4-dichlorophenoxy) pyrimidines.

Also following the procedure of Example 22 but substituting for the2,4-diamino-6-(2,4-dichlorophenoxy)- pyrimidine,2,4-diamino-6-phenoxypyrimidine and each of the above mentioned 2,4diamino 6 halophenoxypyrimidines, there are obtained5-bromo-2,4-diamino-6 phenoxypyrimidine and the corresponding5-bromo-2,4- diamino-6-halophenoxypyrimidines, respectively.

Example 23 .6-am in0-5 -brom0-4- (2,4-dish loroplzenoxy-1,2-dihydr0-1-hydr0xy-2-imin0pyrimidine A solution of5-bromo-2,4-diamino-6-(2,4-dichlorophenoxy) pyrimidine ,21.0 g.),acetone (400 ml.), and ethanol (100 ml.) was cooled to 0 C. During 25minutes, m-chloroperbenzoic acid (24.0 g.) was added with stirring, themixture being maintained at about 0 C. The mixture was stirred for anadditional 4 hours, and was then filtered into a solution of potassiumhydroxide (9.2 g. of in 1500 ml. of water. The combined filtrate andsolution were stirred, and the resulting solid was filtered andrecrystallized from 600 ml. of acetonitrile to give6-amino-5-bromo-4(2,4-dichlorophenoxy)- 1,2dihydro-1-hydroxy-2-iminopyrimidine.

Following the procedure of Example 23, each of the above-mentioned 5halo 2,4-diamino-6-phenoxypyrimidines and5-halo-2,4-diamino-6-halophenoxypyrimidines is transformed to thecorresponding 6-amino-1,2-dihydro- 5 halo1-hydroxy-2-imino-4-phenoxypyrimidine and 6 amino 1,2dihydro-5-halo-4-halophenoxy-1-hydroxy-2- iminopyrimidines,respectively.

Example 24 .6-amino-5 -br0m0-] ,Z-dihydrO-I -hya'r0xy-2-imin0-4-(l-pyrrolidinyl) pyrimidine A mixture of6-amino-5-bromo-4-(2,4-dichlorophenoxy)-l,2-dihydro-1-hydroXy-Z-iminopyrimidine(3.5 g.) and pyrrolidine (25 ml.) was heated at 70 C. for 2 hours. Thereaction mixture was cooled, and the solid was filtered, washedsuccessively with pyrrolidine and diethyl ether, and dried to give6-amino-5-bromo-1,2- dihydro-1-hydroxy-2-imino-4-( l-pyrrolidinyl)pyrimidine.

Following the procedure of Example 24 but using in place of thepyrrolidine, each of the above-mentioned primary and secondary includingheterocyclic amines,

, there are obtained the corresponding 6-amino-5-bromo-1,2-dihydro-1-hydroxy-2-iminopyrimidines substituted at the 4-p0sitionwith mono-substituted and disubstituted moieties, respectively.

Example 25.-6-amin0-5- (p-chlorophenyl) thio -1,2-dihydro-1-hydr0xy-2-imin0-4- (1 -pyrr0lidinyl) pyrimidine A mixture ofp-chlorothiophenol (2.3 g.) dimethylformamide (15 ml.) and sodiumhydroxide (0.2 g.) was stirred under nitrogen until solution wascomplete, after which 6-amino-5-bromo-1,2-dihydro-l-hydroxy-Z-imino-4-(l-pyrrolidinyl)-pyrimidine (1.5 g.) was added. The resulting mixturewas heated at 95 C. for 3 hours, and was then filtered. The filtrate wascooled to 25 C. and mixed with a solution of sodium hydroxide (0.6 g.)in 100 ml. of water. That mixture was filtered, and the filtrate wasallowed to stand several hours. Refillration gave a filter cake whichwas recrystallized from acetonitrile to give 6 amino-5(p-chlorophenyl)thio]-l,2-dihydro-1-hydroxy 2-imino-4-( l-pyrrolidinyl)pyrimidine.

Following the procedure of Example 25 but substituting for thep-chlorothiophenol, thiophenol; p-meihylthiophenol; o-ethylthiophenol;m-bromothiophenol; and fiuorothiophenol, there are obtained6-amino-1,2-dihydro-l-hydroxy-2-imino-5-phenylthio-4- (l-pyrrolidinyl)pyrimidine;

6-amino-l,2-dihydro-1-hydroxy-2-imino-5 (p-methylphenyl) thio] -4-(l-pyrrolidinyl) pyrimidine;

6-amino-l,2-dihydro-5-[ (o-ethylphenyl)thio] -1-hydroxy- 2-imino-4-(l-pyrrolidinyl)pyrimidine;

6-amino-5-[ (m-bromophenyl) thio]-1,2-dihydro-1- hydroxy-2-imino-4-l-pyrrolidinyl) pyrimidine;

and

6-amino-1,2-dihydro-5- (o-fiuorophenyl) thio] -1-hydroxy- 2-imino-4-(l-pyrrolidinyl)pyrimidine, respectively.

Also following the procedure of Example 25 but substituting for the6-amino-5-bro1no-1,2-dihydro-l-hydroxy- 2-imino-4-(l-pyrrolidinyl)pyrimidine, each of the abovementioned 6 aminohalo-l,2-dihydro-l-hydroxy-2- iminopyrimidines substituted at the4-position with monosubstiiuted and disubstituted including heterocyclicamino moieties, there are obtained the corresponding 6-amino-5- [(pchlorophenyl)thio] 1,2-dihydro-hydroxy-2-iminopyrimidines, substitutedat the 4-position as in the reactant.

Also following the procedure of Example but substituting for thecombination of the 6-amino-5-bromo-1,2- dihydro-1-hydroxy-2-imino-4-(1pyrrolidinyl)pyrimidine and p-chlorothiophenol, each of theabove-mentioned 6- amino-S-halo-l,2-dihydro-1-hydroxy-2 iminopyrimidinessubstituted at the 4-position with mono-substituted and disubstitutedincluding heterocyclic amino moieties and each of the otherabove-mentioned thiophenols within the scope of Formula XXIII, above,there are obtained the corresponding 6-amino-1,2-dihydro 1 hydroxy-Z-iminopyrimidines, substituted at the 4-position as in the pyrimidinereactant and substituted at the 5-position with an arylthio moietycorresponding to the particular thiophenol used.

Example 26.-6-amino-I,Z-dihydro-IJtydroxy-Z-imino-4,5-di-(1-pyrr0lidinyl)pyrimidine A mixture of6-amino-5-bromo-1,Z-dihydro-l-hydroxy- 2-imino-4-(l-pyrrolidinyl)pyrimidine (2.7 g.) and pyrrolidine (25 ml.) was heated in a sealed,heavy-wall, glass tube in a 120 C. oil bath for 2.5 hours. The tube wasthen cooled and opened, and the reaction mixture was evaporated to a dryresidue under reduced pressure. That residue was extracted 4 times with100-ml. portions of chloroform. The combined chloroform extracts weredried with anhydrous sodium sulfate and evaporated to give a solidresidue. The latter residue was recrystallized from acetonitrile to give6-amino-1,2 dihydro-1-hydroxy-2- imino-4,5-di-( l-pyrrolidinyl)pyrimidine.

Addition of absolute ethanol containing one equivalent of hydrogenchloride to an absolute ethanol solution of6-amino-1,Z-dihydro-l-hydroxy-Z-imino 4,5 di-(l-pyrrolidinyl)pyrimidine, followed by addition of about 4 volumes of diethyl ether,gives the corresponding monohydrochloride. Similar use of ethanolcontaining 2 equivalents of hydrogen chloride gives the correspondingdihydrochloride. Similar use of benzoic acid, maleic acid, lactic acid,phosphoric acid, sulfuric acid, and succinic 4.0 acid gives thecorresponding monoand diacid addition salts.

Following the procedure of Example 26 but substituting for thepyrrolidine, each of the above-mentioned primary and secondary includingheterocyclic amines, there are obtained the corresponding free bases andacid addition salts of 6-amino-1,2-dihydro-1-hydroxy-2-amino-4-(1pyrrolidinyl) pyrimidines substituted at the 5-position withmonosubstituted and disubstituted including heterocyclic amino moieties.

Also following the procedure of Example 26 but substituting for thecombination of the 6-amino-5-bromo- 1,Z-dihydro-1-hydroxy-2-imino-4-(1pyrrolidinyl)pyrimidine and the pyrrolidine, each of the above-mentioned6-amino-5-bromo-1,2 dihydro 1-hydroxy-2-iminopyrimidines substituted atthe 4-position with mono-substituted or disubstituted includingheterocyclic amino moieties and each of the above-mentioned primary andsecondary including heterocyclic amines, there are obtained thecorresponding free bases and acid addition salts of6-amino-1,2-dihydro-1-hydroxy 2 iminopyrimidines substituted at the4-position and at the 5-position with the same or differentmono-substituted and disubstituted including heterocyclic aminomoieties.

Example 27.-6-acetamid0-2-acetylimin0-1,2-dihydro-I-hydr0xy-4-pipcridinopyrimidine A mixture of6-amino-1,2-dihydro-l-hydroxy-Z-imino- 4-piperidinopyrimidine (4.1 g.),acetic anhydride (4.0 ml.), and diethyl ether (200 ml.) was stirred at25 C. for 60 hours. The solid which formed was filtered and washed withether to give 5.5 g. of a solid, 3.0 g. of which was recrystallized from400 ml. of dimethylformamide to give 1.5 g. of6-acetamido-2-acetylimino-1,2-dihydro- 1-hydroxy-4-piperidinopyrimidine;M.P. 204205 C.

A/zalysis.-Calcd. for C13H19N503Z C, H, N, 23.88. Found: C, 52.81; H,6.23; N, 24.06.

(ethanol) 241 m (e=35,100); 291.5 In, (6 21,-

000 328 m t #6000 (0.01 N H 241 m (e=30,850); 291 m (-e=l9,050); 51 sh355 m (e=4050). (0.01 N KOH) 233 m (=32,650);261m/L (6:13,-

950); 286 m (e=12,500). (chloroform) 296 m (e=20,050); 341 III/L (e:5600). I.R.: (principal bands; mineral oil mull) 3160, 3060, 1710,1680, 1630, 1565, 1535, 1480, 1255, 1225, 1205, 1180, 1130 cmf Followingthe procedure of Example 27 but using acetyl chloride in place of theacetic anhydride the same product is obtained. Also following theprocedure of Example 27 but using in place of the acetic anhydride,ropionic anhydride; crotonic anhydride; cyclohexanecarboxylic anhydride;isobutyryl chloride, decanoyl chloride; phenylacetyl chloride;3-methoxybutyric anhydride; p-tert-butylcyclohexanecarbonyl chloride;and p-nitrophenylacetyl chloride, there are obtained1,Z-dihydro-1-hydroxy-4-piperidino-G-propionamido 2propionyliminopyrimidine; 6- crotonamido-Z-crotonoylimino1,2-dihydro-1-hydroxy-4- piperidinopyrimidine; 6cyclohexanecarboxyamido-Z-cyclohexanecarbonylimino1,2dihydro-1-hydroxy-4-piperidinopyrimidine;1,Z-dihydro-1-hydroxy-6-isobutyramido-2-isobutyrylimino-4-pipcridinopyrimidine; 6-decanamido-Z-decanoylimino-1,2-dihydro 1 hydroxy-4-piperidinopyrimidine;1,2-dihydro-1-hydroxy-4-piperidinO-G-phenylacetamido-Z-phenylacety1iminopyrimidine;1,2-dihydro-1- hydroxy-6-(3-methoxybutyrarnido) 2 (3methoxybut-yrylimino) 4 piperidinopyrimidine;6-(p-tert-butylcyclohexanecarboxamido) 2(p-tcrt-butylcyclohexanecarbonylimino)-1,2- dihydro 1hydr0xy-4-piperidin0- pyrimidine, and1,2-dihydro-l-hydroxy-6-(p-nitrophenylacetamido) 2(p-nitrophenylacetylimino)-4-piperidinopyrimidine, respectively.

